4,4-disubstituted-1,4-dihydro-2h-3,1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same

ABSTRACT

The present invention relates to benzoxazinones of formula I:                    
     or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as an assay standard or reagent, and intermediates and processes for making the same.

This application is a division of application Ser. No. 09/176,491, filed Oct. 21, 1998, now U.S. Pat. No. 6,140,499, which is a division of application Ser. No. 08/942,031, filed Oct. 1, 1997, now U.S. Pat. No. 5,874,430, which claims the benefit of U.S. Provisional Application No. 60/045,138, filed Apr. 30, 1997 and U.S. Provisional Application 60/027,137, filed Oct. 2, 1996.

FIELD OF THE INVENTION

This invention relates generally to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.

BACKGROUND OF THE INVENTION

Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.

The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.

At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield th mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particles's maturing into a virus that is capable of full infectivity.

The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.

There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pool protein by HIV protease.

Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion's genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA. HIV-1 replication can be stopped.

A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxythymidinene (d4T), 2′, 3′-dideoxyinosine (ddI), and 2′,3′-dideoxy-3′-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.

Non-nucleoside HIV reverse transcriptase inhibitors have also been discovered. As an example, it has been found that certain benzoxazinones are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. U.S. Pat. No. 5,519,021, the contents of which are hereby incorporated herein by reference, describe reverse transcriptase inhibitors which are benzoxazinones of the formula:

wherein X is a halogen, Z may be O. However, benzoxazinones of this type are specifically excluded from the present invention.

In U.S. Pat. No. 5,519,021 one compound in particular, (−) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (NNRTI), shown below,

has been found to be a potent and specific inhibitor of HIV-1 reverse transcriptase worthy of further study. NNRTI is described in Step D of Example 6 of the disclosure. Rat, monkey, and human microsomes treated with NNRTI, during investigation of the cytochrome P450 metabolism of NNRTI, produced a metabolite which was discovered to also be a potent inhibitor of HIV reverse transcriptase. This metabolite, its stereoisomer, stereoisomeric mixtures, and derivatives thereof are an embodiment of the present invention.

Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.

It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability or potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):

wherein A, W, X, Y, Z, R¹ and R² are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I:

or stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

A is O or S;

W is N or CR³;

X is N or CR⁴;

Y is N or CR⁵;

Z is N or CR⁶;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

also, provided that if X is CR⁴ and R⁴ is F, Cl, Br, or I, then:

(a) at least one of W, Y, and Z is other than CH;

(b) R² is —OCHR⁷R⁸ or —NHCHR⁷R⁸;

(c) if R² is —C≡C-R⁸, then R⁸ is C₃₋₇ cycloalkyl substituted with 1 R⁹; or

(d) any combination of (a), (b), and (c);

R¹ is selected from CF₃, CF₂H, C₂F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R² is selected from —QCHR⁷R⁸, —QCHR⁷C≡C-R⁸,—QCHR⁷C═C-R⁸, —Q(CH₂)_(p)CHR⁷R⁸, —C≡C-R⁸, —CH═CR⁷R⁸, —(CH₂)_(p)CHR⁷R⁸, —CHR⁷C≡C-R⁸, —CHR⁷CH═CHR⁸, and CH═CHCHR⁷R⁸;

provided that when R¹ is C₁₋₄ alkyl, then R² is —C≡C-R⁸;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic hetercycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰;

alternatively, R³ and R⁴ together form —OCH₂O—;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form —OCH²O—or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, —CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰;

R⁹ is selected from D, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷R^(7a), CHO, C(O)CH₃, C(O)NH₂;

Q is selected from O, S and NH; and,

p is selected from 0, 1, and 2.

[2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is selected from CF₃, CF₂H, C₂F₅, C₁₋₃ alkyl, C₃₋₅ cycloalkyl; and,

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.

[3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is selected from CF₃, CF₂H, C₂F₅, C₂H₅, isopropyl, cyclopropyl;

R³ is selected from H, F, Cl, Br, I, OCH₃, CH₃;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R₇, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form —OCH₂O—;

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, —CN, F, CF₃, CH₃, and C(O)NH₂;

R⁷ is selected from H and CH₃;

R^(7a) is selected from H and CH₃;

R^(7b) is CH₃;

R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰;

R⁹ is selected from D, OH, OCH₃, CH₃, and F;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃; and,

p is selected from 1 and 2.

[4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

A is O;

R¹ is selected from CF₃, CF₂H, C₂F₅;

R² is selected from —OCHR⁷R⁸, —OCH₂C≡C-R⁸, —OCH₂C═C-R⁸, —OCH₂CHR⁷R⁸, —C≡C-R⁸, —CH═CR⁷R⁸, —CH₂CHR⁷R⁸, —CH₂C≡C-R⁸, CHR⁷CH═CHR⁸, and CH═CHCHR⁷R⁸;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C≡CH, OCH₃, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), C(O)OR⁷, NR⁷SO₂R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form —OCH₂O—; and,

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷R^(7a), C(O)CH₃, and C(O)NH₂.

[5] In a further preferred embodiment, the compound of the present invention is selected from:

(+/−)-6-Chloro4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(−)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-6-Chloro-4-(2-(furan-2-yl)ethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-4-(1′-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/−)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; and,

(+/−)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

[6] In a second embodiment, the present invention provides a novel compound of formula II:

or a salt or stereoisomer thereof, wherein:

A is O or S;

W is N or CR³;

X is N or CR⁴;

Y is N or CR⁵;

Z is N or CR⁶;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₂H, C₂F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R¹⁰;

alternatively, R³ and R⁴ together form —OCH₂O—;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form —OCH₂O—or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, —CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷R^(7a), CHO, C(O)CH₃, C(O)NH₂;

p is selected from 0, 1, and 2.

[7] In another preferred embodiment, the present invention provides a novel compound of formula II, wherein:

A is O; and,

R^(1a) is selected from CF₃, CF₂H, C₂F₅, C₁₋₃ alkyl, C₃₋₅ cycloalkyl.

[8] In a more preferred embodiment, the present invention provides a novel compound of formula II, wherein:

R^(1a) is selected from CF₃, CF₂H, C₂F₅, C₂H₅, isopropyl, cyclopropyl;

R³ is selected from H, F, Cl, Br, I, OCH₃, CH₃;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ R⁴ together form —OCH₂O—;

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, —CN, F, CF₃, CH₃, and C(O)NH₂;

R⁷ is selected from H and CH₃;

R^(7a) is selected from H and CH₃;

R^(7b) is CH₃;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃; and,

p is selected from 1 and 2.

[9] In an even more preferred embodiment, the present invention provides a novel compound of formula II, wherein:

R^(1a) is selected from CF₃, CF₂H, C₂F₅;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C≡CH, OCH₃, OCF₃, —CN, NO₂, CHO, C(O)Cl₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), C(O)OR⁷, NR⁷SO₂R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form —OCH₂O—; and,

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷R^(7a), C(O)CH₃, and C(O)NH₂.

[10] In a third embodiment, the present invention provides a novel process for making a compound of formula II:

or a salt or stereoisomer thereof, comprising:

(a) contacting a compound of formula III:

or a suitable salt form thereof, with a carbonyl or thiocarbonyl delivering agent in the presence of a suitable solvent, wherein:

A is O or S;

W is N or CR³;

X is N or CR⁴;

Y is N or OR⁵;

Z is N or OR⁶;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₂H, C₂F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰;

alternatively, R³ and R⁴ together form —OCH₂O—;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form —OCH₂O— or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, —CN, F, Cl, Br, I, NO₂, (F₃, CHO, C₁₋₃ alkyl, and C(O)NH₂;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷R^(7a), CHO, C(O)CH₃, C(O)NH₂;

Q is selected from O, S and NH; and,

p is selected from 0, 1, and 2.

[11] In another preferred embodiment, in formulae II and III,

A is O;

R^(1a) is selected from CF₃, CF₂H, C₂F₅; R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C≡CH, OCH₃, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), C(O)OR⁷, NR⁷SO₂R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form —OCH₂O—; and,

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, —CN, F, CF₃, CH₃, and C(O)NH₂;

R⁷ is selected from H and CH₃;

R^(7a) is selected from H and CH₃;

R^(7b) is CH₃;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃;

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷R^(7a), C(O)CH₃, and C(O)NH₂; and,

p is selected from 1 and 2.

[12] In another more preferred embodiment, the carbonyl delivering agent is selected from phosgene, carbonyldiimidazole, chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate.

[13] In another even more preferred embodiment, the carbonyl delivering agent is phosgene and the solvent is toluene.

[14] In another more preferred embodiment, in step (a) a base is present and is selected from trimethylamine, triethylamine, and N,N-disopropylethylamine.

[15] In a fourth embodiment, the present invention provides of process for making a compound of formula Ia:

or a stereoisomer or pharmaceutically acceptable salt form thereof, comprising:

(a) contacting a nucleophile, R^(2b), with a compound of formula II:

or stereoisomer thereof in a suitable solvent, wherein:

R^(2b) is selected from R⁸R⁷CH—OH, R⁸R⁷CH—OM, R⁸R⁷CHNH₂, R⁸R⁷CHNH—M, R⁸—O≡C—M, R⁷R⁸C═CH—M, R⁸R⁷CH(CH₂)_(p)—M, R⁸CH═CHC(H) (R⁷)—M, R⁸R⁷CHCH═CH—M;

M is selected from Na, Li, Mg, Zn, Cu, Pd, Pt, Sn, Al, and B;

A is O or S;

W is N or CR³;

X is N or CR⁴;

Y is N or CR⁵;

Z is N or CR⁶;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₂H, C₂F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R^(2a) is selected from —QCHR⁷R⁸, —QCHR⁷C≡C—R⁸, —QCHR⁷C═C—R⁸, —Q(CH₂)_(p)CHR⁷R⁸, —C≡C—R⁸, —C═CR⁷R⁸, —(CH₂)_(p)CHR⁷R⁸, —CHR⁷C≡C—R⁸, —CHR⁷CH═CHR⁸, and CH═CHCHR⁷R⁸;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰;

alternatively, R³ and R⁴ together form —OCH₂O—;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form —OCH₂O— or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, —CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰;

R⁹ is selected from D, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷R^(7a), CHO, C(O)CH₃, C(O)NH₂;

Q is selected from O, S and NH; and

p is selected from 0, 1, and 2.

[16] In another preferred embodiment, in formulae Ia and II,

A is O;

R^(1a) is selected from CF₃, CF₂H, C₂F₅;

R^(2a) is selected from —OCHR⁷R⁸, —OCH₂C≡C—R⁸, —OCH₂C═C—R⁸, —OCH₂CHR⁷R⁸, —C≡C—R⁸, —CH═CR⁷R⁸, —CH₂CHR⁷R⁸, —CH₂C≡C—R⁸, CHR⁷CH═CHR⁸, and CH═CHCHR⁷R⁸;

R³is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C≡CH, OCH₃, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), C(O)OR⁷, NR⁷SO₂R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form —OCH₂O—; and,

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, —CN, F, CF₃, CH₃, and C(O)NH₂;

R⁷ is selected from H and CH₃;

R^(7a) is selected from H and CH₃;

R^(7b) is CH₃;

R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰;

R⁹ is selected from D, OH, OCH₃, CH₃, and F;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃;

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷R^(7a), C(O)CH₃, and C(O)NH₂; and ,

p is selected from 1 and 2.

[17] In another more preferred embodiment, in step (a), the compound of formula II is added to a solution containing the nucleophile.

[18] In another more preferred embodiment, in step (a), R^(2b) is R⁸—C≡C—M; and M is selected from Li, Mg, and Zn.

[19 ] In another even more preferred embodiment, in step (a), R⁸—C≡C—M is formed in situ by addition of a strong base to a solution containing R⁸—C≡C—H.

[20] In another further preferred embodiment, in step (a), the strong base is selected from n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium.

[21] In another further preferred embodiment, the compound of formula Ia is:

the compound of formula Ia is:

the nucleophile R^(2b) is lithium cyclopropylacetylide; and the solvent is THF.

[22] In a fifth embodiment, the present invention provides a novel method of making a compound of formula IIIb:

or stereoisomer or salt form thereof, comprising:

(a) contacting a compound of formula IIIa:

with R^(1a)-TMS and an anion, wherein:

the anion is a fluoride or oxyanion and is selected from tetrabutylammonium fluoride, sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride, potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate;

Pg is an amine protecting group;

W is N or CR³;

X is N or CR⁴;

Y is N or CR⁵;

Z is N or CR⁶;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₃CF₂, and CF₃CF₂CF₂;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂,CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰;

alternatively, R³ and R⁴ together form —OCH₂O—;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form —OCH₂O— of a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, —CN, F, Cl, Br, I, NO₂, CR₃, CHO, C₁₋₃ alkyl, and C(O)NH₂;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷R^(7a), CHO, C(O)CH₃, C(O)NH₂;

p is selected from 0, 1, and 2.

[23] In another preferred embodiment, in formulae IIIa and IIIb,

the R^(1a)-TMS is trifluoromethyl trimethylsilane;

the anion is tetrabutylammonium fluoride;

Pg is trityl;

R^(1a) is CF₃;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C≡CH, OCH₃, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), C(O)OR⁷, NR⁷SO₂R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form —OCH₂O—; and,

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, —CN, F, CF₃, CH₃, and C(O)NH₂;

R⁷ is selected from H and CH₃;

R^(7a) is selected from H and CH₃;

R^(7b) is CH₃;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃;

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷R^(7a), C(O)CH₃, and C(O)NH₂; and,

p is selected from 1 and 2.

[24] In another more preferred embodiment, the process further comprises:

(b) contacting a compound of formula IIIb with an oxidizing agent to form compound of formula IIIc:

[25] In another even more preferred embodiment, the oxidizing agent is MnO₂.

In a fifth embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a sixth embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a seventh embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

(a) a compound of formula I; and

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

In another preferred embodiment, the reverse transcriptase inhibitor is a nucleotide reverse transcriptase inhibitor.

In another more preferred embodiment, the nucleotide reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.

In an even more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, rescriptor, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.

In a still further preferred embodiment, the nucleoside reverse transcriptase inhibitor is AZT.

In another still further preferred embodiment, the protease inhibitor is indinavir.

In a eighth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

(a) a compound of formula I; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

In a ninth embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I.

In a tenth embodiment, the present invention to provides a novel a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

DEFINITIONS

As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific sterochemistry or isomer form is specifically indicated. The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.

The reactions of the synthetic methods claimed herein may be, as noted herein, carried out in the presence of a suitable base, said suitable base being any of a variety of bases, the presence of which in the reaction facilitates the synthesis of the desired product. Suitable bases may be selected by one of skill in the art of organic synthesis. Suitable bases include, but are not intended to be limited to, inorganic bases such as alkali metal, alkali earth metal, thallium, and ammonium hydroxides, alkoxides, phosphates, and carbonates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, thallium hydroxide, thallium carbonate, tetra-n-butylammonium carbonate and ammonium hydroxide. Suitable bases also include organic bases, including but not limited to aromatic and aliphatic amines, such as pyridine; trialkyl amines such as triethylamine, N,N-diisopropylethylamine, N,N-diethylcyclohexylamine, N,N-dimethylcyclohexylamine, N,N,N′-triethylenediamine, N,N-dimethyloctylamine; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,4-diazabicyclo[2.2.2]octane (DABCO); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); tetramethylethylenediamine (TMEDA); and substituted pyridines such as N,N-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine, 4-piperidinopyridine.

Suitable halogenated solvents include: carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, or fluorobenzene.

Suitable ether solvents include, but are not intended to be limited to, dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene gylcol dimethyl ether, or t-butyl methyl ether.

Suitable protic solvents may include, by way of example and without limitation water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol.

Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

Suitable hydrocarbon solvents include, but are not intended to be limited to, benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

As used herein, the term “amine protecting group” (or “N-protected”) refers to any group known in the art of organic solvents for the protection of amine groups. As used herein, the term “amine protecting group reagent” refers to any reagent known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected with an amine protecting group. Such amine protecting groups include those listed in Greene and Wuts, “Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1991) and “The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl (trityl) and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.

Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methyloxycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolylmethyloxycarbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; N′-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl; phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl; 5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; or methanesulfonamide.

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. “Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. “Alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo and iodo. “Counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.

As used herein, “aryl” or “aromatic residue” is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic which may be saturated partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 6-membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, than these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 6-membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, “HIV reverse transcriptase inhibitor” is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, rescriptor (delavirdine, Pharmacia and Upjohn), viviradine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine, L-697,661, LY 73497, and Ro 18,893 (Roche).

As used herein, “HIV protease inhibitor” is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), and U-103017 (Pharmacia and Upjohn). Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT application No. US96/03426.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p 1418, the disclosure of which is hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

“Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contempleted by the present invention.

“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s) provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

“Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

SYNTHESIS

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Each of the references cited below are hereby incorporated herein by reference.

Scheme 1 illustrates a method of making 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting from an appropriately substituted 2-aminobenzoic acid. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R¹-substituted ketone. Subsequent addition of another metallic species provides the alcohol which is readily cyclized with phosgene or an equivalent thereof.

Scheme 2 describes a means of obtaining 4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting from an appropriately substituted aniline. After iodination, the trifluoromethyl group can be introduced using a strong base and ethyl trifluoroacetate. The second 4-substituent can then be added through anion attack on the ketone or using other means well known to those of skill in the art. Cyclization can be then be completed as in Scheme 1.

Because certain benzo-substituents are incompatible with the methods of Schemes 1 and 2, it may be necessary to protect these groups before forming the benzoxazinone. In Scheme 3 there is shown a means of obtaining carbonyl-substituted 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones. After iodination of an acetyl-aniline, the acetyl group is protected by means well known to those of skill in the art, such as using 1,3-propanedithiol. The same procedures as in Scheme 2 are used to arrive at the cyclized product. Deprotection of the ketone can then be achieved using HgCl₂ and HgO or other means well known to those of skill in the art.

A method for forming 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones, wherein R² is a vinyl or alkynyl group, is described in Scheme 4. Starting from an appropriately substituted ketone which can be obtained using the procedure of Scheme 1 or 2, an acetylide is added. The product can be deprotected and cyclized to obtain the alkynyl-substituted material. Alternatively, the vinyl compounds can be obtained by reduction of the alkyne with a reducing agent, such as LiAlH₄, deprotection by standard means, and cyclization.

Scheme 5 describes an alternate route to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from anilines, wherein the aniline is protected, ester addition is accomplished using a strong base and the amine protecting group is removed. The R² group can then be added, e.g. via an acetylide, followed by cyclization.

An intermediate useful in the preparation of the presently claimed compounds is 2-trifluoroacetylaniline. The starting 4-chloro-2-trifluoroacetylaniline can be made as shown in Scheme 2. Reduction and reoxidation removes the chloro group leaving the desired intermediate.

Scheme 7A describes a novel method of making 2-trifluoroacetylanilines as well as how these compounds can be further modified to make the presently claimed compounds. The protected aldehyde can be made from the N-methoxy-N-methyl amide of Scheme 1, by addition of a protecting group, preferably trityl, and reduction of the amide to the aldehyde. Other protecting groups known to those of skill in the art can be used in place of the shown trityl group.

Scheme 7B illustrates specific steps of Scheme 7A. Intermediate IIIb (R^(1a) is selected from CF₃, CF₃CF₂, and CF₃CF₂CF₂) is useful for making some of the presently claimed compounds. Pg is an amine protecting group as defined previously, preferably trityl (triphenylmethyl). The protected or unprotected aminobenzaldehyde, preferably protected, is treated with a perfluoralkyl trimethylsilane, preferably trifluoromethyl trimethylsilane, followed by fluoride anion, preferably tetrabutylammonium fluoride. In the same fashion, CF₃CF₂TMS, CF₃CF₂CF₂TMS can also be used to prepare the appropriately substituted ketones. Other sources of fluoride anion such as sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride as well as oxyanionic species such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate can also be used.. Aprotic solvents such as DMF and THF can be used, preferably THF. The amount of perfluoralkyl trimethylsilane used can be from about 1 to about 3 equivalents with an equivalent amount of fluoride anion or oxyanionic species. The reaction can be typically carried out at temperatures between about −20° C. to about 50° C., preferably about −10 to about 10° C., more preferably about 0° C.

Conversion of IIIb to IIIc can be achieved by using an oxidizing agent well known to one of skill in the art such as MnO₂, PDC, PCC, K₂Cr₂O₇, CrO₃, KMnO₄, BaMNO₄, Pb(OAc)₄, and RuO₄. A preferred oxidant is MnO₂. Such conversion can be performed in an aprotic solvent like THF, DMF, dichloromethane dichloroethane, or tetrachloroethane, preferably dichloromethane.

Scheme 8 illustrates a method of forming aza-4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from an appropriately substituted amino-pyridine. Carbonyl addition to the pyridine can be accomplished using a strong base and an appropriate ketone. Addition of base can afford the cyclized product.

An additional means of making 4-alkynyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones is shown in Scheme 9. The alkyne group is added to the keto-aniline via a Grignard type addition, followed by cyclization. The alkyne group of the product can then be modified to obtain the desired compound.

In addition to the methods of obtaining keto-anilines described in Schemes 1 and 2, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 10. This reaction is accomplished by using an anionic nucleophile of the group R^(1a). See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219.

It is preferred that the stoichiometry of the isatoic anhydride reagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0) of anion (or anion precursor) is preferred to force the conversion and improve the isolated yield. Preferably, the temperature used is from −20 to +35° C., with temperature below 0° C. being more preferred and −20° C. being even more preferred. Reactions are run to about completion with time dependent upon inter alia nucleophile, solvent, and temperature. Preferably this nucleophilic addition is run in THF, but any aprotic solvent would be suitable. Reaction with the active nucleophilic anion is the only criterion for exclusion of a solvent.

An intermediate in this novel process is the chlorobenzoxazinone (II) which can be synthesized from the corresponding keto-aniline as shown in Scheme 11. The preparation of compounds of formula II works well with either the free base of the keto-aniline or its hydrochloride hydrate, though the free base is preferred due to its inherent reactivity. The carbonylation or thiocarbonylation reagent is selected from the group: phosgene (COCl₂), thiophosgene (CSCl₂), carbonyldiimidazole (CDI), chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate. Preferably, phosgene is used as the carbonylation reagent.

About 1, 2, 3, 4, or 5 equivalents of carbonylation or thiocarbonylation reagent are used, preferably from about 1 to about 2.5, even more preferably from about 1 to 2, and still further preferably about 1, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents. With volatile reagents like phosgene more than one equivalent can help the conversion and yield of the reaction but is not necessary to effect transformation.

Solvents such as toluene may be used. Additional nonreactive solvents, such as ethers (e.g., dimethyl ether and diethyl ether), hydrocarbons (e.g., hexane and cyclohexane) or other aromatic solvents (e.g., benzene, anisole, or quinoline) can also be used. Solvents with boiling points around that of toluene or higher are preferred. Use of such solvents allows heat to be applied to the reaction to promote the cyclization. When the preferred carbonylation reagent, phosgene is use, heat helps drive off the HCl generated and promote the closure reaction. When toluene is used, it is preferred to run the reaction near toluene's boiling point. However, one of ordinary skill in the art would recognize that too high of a temperature may decompose the product. In addition, too low of a temperature may cause an undesirably slow reaction. Reaction progress may be determined by the decoloration of the reaction mixture (indicating consumption of starting material) and confirmation of completeness by proton NMR. The reaction may be catalyzed by the addition of an acid scavenger such as an amine base (e.g., triethylamine or Hunigs base) or an inorganic base (e.g., sodium carbonate or potassium).

Scheme 12 describes routes to a variety of R²- substituted compounds of formula Ia by reacting a nucleophile (R^(2b)) with a compound of formula II (preferably R^(1a) is CF₃). This displacement reaction is quite versatile and a large range of nucleophiles can be used. Preferably the nucleophile is an amine (e.g., R⁸R⁷CHNH) or a metallic species selected from R⁸R⁷CH—OM, R⁸R⁷CH—SM, R⁸R⁷CHNH—M, R⁸—C≡C—M, R⁷R⁸C═CH—M, R⁸R⁷CH(CH₂)_(p)—M, R⁸CH═CHC(H) (R⁷)—M, and R⁸R⁷CHCH═CH—M. In addition, R⁸R⁷CH—OH and its thiol analog, R⁸R⁷CH—SH, can be used without formation of their corresponding anions. The metallic moiety, M, is selected from the group Na, Li, Zn, Mg, Cu, Pd, Pt, Sn, Al, and B, preferably Li, Mg, or Zn.

If an metallic nucleophile is used, it may be made in situ by methods known to those of skill in the art or formed by methods known to those of skill in the art and then added to a solution. In either case, it is preferred that the compound of formula II is added to a solution containing the nucleophile.

Preferably, the nucleophile is an acetylide (i.e., R⁸—C≡C—M) with Li, Mg, or Zn as the counterion. Acetylides are well known in the art. Preferably, R⁸—C≡C—M is formed in situ by addition of a strong base to a solution containing R⁸—C≡C—H. Strong bases are well known to those of skill in the art and include, but are not limited to n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium. Preferably, the strong base is n-butyl lithium. The acetylide may also be made in situ by addition of a strong base to a dihalo-olefin (e.g., Br₂C═CHR⁸).

In the nucleophilic addition reactions the stochiometery is preferably about one equivalent of benzoxazinone to about 1.0 to 2.5 equivalents of nucleophile (e.g., 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5). More preferable about 1.8 to 2.4 equivalents are used. Even more preferably, 2.1 equivalents of nucleophile are used. It is noted that less than one equivalent may be used, but care must be taken as N—H deprotonation reaction may compete with nucleophilic addition. It is preferable to run the additions from −40 to 0° C., more preferably about −20° C. The solvent used is preferably THF, but any aprotic solvent, such as dimethyl ether, diethyl ether, benzene, or toluene, should be suitable. Non-reaction with the nucleophile, specifically the nucleophilic anion, is the only criterion for exclusion of a solvent.

An additional example of the utility of the final nucleophilic addition step of the present invention is shown in Scheme 13.

A preferred example of the present process is shown in Scheme 14.

In Scheme 14, the preferred temperature of the carbonylation reaction is from about 104 to about 110° C. and the preferred temperature of the acetylide addition is about −20° C.

One enantiomer of a compound of Formula I may display superior activity compared with the other. Thus, both of the following stereochemistries are considered to be a part of the present invention.

When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940.

Another method of forming a compound wherein Z is C(OH) involves incubating NNRTI, or a derivative thereof, in microsomes obtained from male rats, male rhesus monkeys or humans, preferably male rats. In addition, it is preferable to orally dose the male rats with NNRTI prior to collection of their livers and microsomal isolation. This procedure will be described in the following Example section.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “° C” for degrees Celsius, “d” for doublet, “dd” for doublet of doublets, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “H” for hydrogen or hydrogens, “hr” for hour or hours, “m” for multiplet, “M” for molar, “min” for minute or minutes, “MHz” for megahertz, “MS” for mass spectroscopy, “nmr” or “NMR” for nuclear magnetic resonance spectroscopy, “t” for triplet, “TLC” for thin layer chromatography, “EDAC” for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, “DIPEA” for diisopropylethylamine, “TBAF” for tetrabutylammonium fluoride, “LAH” for lithium aluminium hydride, and “TEA” for triethylamine.

Example 1

Preparation of (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A Preparation of 4′-Chloro-2′-methoxy-2,2-dimethylpropionanilide

A stirred solution of 22.6 g (100 mmol) of stannous chloride dihydrate in 40 mL of absolute ethanol was heated to reflux and treated with 3.75 g (20 mmol) of 5-chloro-2-nitroanisole in 20 mL of 1:1 ethanol-tetrahydrofuran over 3 min. Stirring at reflux for an additional 10 minutes gave a clear solution which was then cooled to 0° C. The mixture was treated with aqueous Na₂CO₃ until a pH of 8-9 was reached. The colloidal suspension was extracted twice with ethyl acetate, and the combined organic extracts were washed with saturated NaHCO₃ then brine. The solution was dried (MgSO₄) and concentrated under reduced pressure. The crude oil was dissolved in 40 mL of CH₂Cl₂ and cooled to 0° C. The solution was treated with 4.2 mL (30 mmol) of triethylamine followed by 2.8 mL (23 mmol) of pivaloyl chloride. After stirring 2 h at 0° C. the mixture was quenched with 0.5 N HCl, and the phases were separated. The aqueous phase was extracted with 100 mL of 1:1 ether-hexanes, and the combined organic extracts were washed sequentially with 0.1 N HCl, dilute K₂CO₃, water, and brine. The solution was dried (MgSO₄) and concentrated under reduced pressure to give 4.68 g (97%) of 4′-chloro-2′-methoxy-2,2-dimethylpropionanilide as an tan solid, mp 66-69° C. ¹H NMR (300 MHz, CDCl₃) δ 8.36(d, 1H, J=8.8 Hz); 8.03(br. s, 1H); 6.94(dd, 1H, J=8.8, 2.2 Hz); 6.86(dd, 1H, J=2.2 Hz); 3.90(s, 3H); 1.32(s, 9H). High resolution mass spec: calculated for C₁₂H₁₇NO₂Cl(M+H)⁺: 242.0948, found: 242.0943. Analysis calculated for C₁₂H₁₆NO₂Cl: C, 59.63; H, 6.67; N, 5.79; Cl, 14.67. Found: C, 59.73; H, 6.67; N, 5.57; Cl, 14.42.

Part B Preparation of 2′-Amino-5′-chloro-3′-methoxy-2,2,2-trifluoroacetophenone

To a stirred, cooled (−20° C.) solution of 12.1 g (50 mmol) of 4′-chloro-2′-methoxy-2,2-dimethylpropionanilide in 150 mL of THF was added 87 mL (115 mmol) of 1.3 M s-BuLi in cyclohexane over 15 min. The dark solution was warmed to 0° C. and stirred for 1.2 h. The solution was re-cooled to −20° C. and treated with 14.3 mL (120 mmol) of ethyl trifluoroacetate over 5 min. The reaction was warmed to 0° C., stirred 15 min., and quenched with saturated aqueous NaHCO₃. The mixture was extracted with hexanes and then with ether, and the combined organic extracts were washed sequentially with 0.5 N HCl, water, and brine. The solution was dried (MgSO₄) and concentrated under reduced pressure to give a dark oil. The crude amide was dissolved in 20 mL of 1,2-dimethoxyethane and treated with 100 mL of 6 N aqueous HCl. The mixture was stirred at reflux for 2 h, cooled to 0° C., and brought to pH 9 with K₂CO₃. The mixture was extracted twice with ether, and the combined organic extracts were washed with brine, dried (MgSO₄), and concentrated under reduced pressure to give an oily solid. This crude product was recrystallized from hexanes and a minimal amount of ethyl acetate to give 7.75 g (61%) of 2′-amino-5′-chloro-3′-methoxy-2,2,2-trifluoroacetophenone as yellow needles, mp 124.5-125.5° C. ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.35(m, 1H); 6.87(br. s, 2H); 6.84(d, 1H, J=1.8 Hz); 3.92(s, 3H). High resolution mass spec: calculated for C₉H₈NO₂ClF₃(M+H)⁺: 254.0196, found: 254.0194. Analysis calculated for C₉H₇NO₂ClF₃: C, 42.62; H, 2.78; N, 5.52; Cl, 13.98. Found: C, 42.52; H, 3.04; N, 5.40; Cl, 13.74.

Part C Preparation of 2′-Amino-5′-chloro-3′-hydroxy-2,2,2-trifluoroacetophenone

To a stirred, cooled (0° C.) solution of 31.2 g (123 mmol) of 2′-amino-5′-chloro-3′-methoxy-2,2,2-trifluoroacetophenone in 150 mL of CH₂Cl₂ was added 550 mL (550 mmol) of 1 M BBr₃ in CH₂Cl₂ over 20 min. The dark solution was stirred 17 h at ambient temperature, re-cooled to 0° C., and fitted with a pressure-equalizing dropping addition funnel and a Claisen adapter connected by rubber tubing to a large water scrubber. The reaction a carefully quenched by dropwise addition of aqueous Na₂CO₃ until a pH of 7-8 was reached. The phases were separated, and the aqueous phase was extracted with 1 liter of 1:1 ether-hexanes. The combined organic phases were washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure to afford 30.1 g (100%) of 2′-amino-5′-chloro-3′-hydroxy-2,2,2-trifluoroacetophenone as a chalky brown solid, mp 120-122° C. ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.36(m, 1H); 6.88(d, 1H, J=1.8 Hz); 6.75(br. s, 2H); 5.78(br. s, 1H). High resolution mass spec: calculated for C₈H₆NO₂ClF₃(M+H)⁺: 240.0039, found: 240.0029.

Part D Preparation of 2′-Amino-5′-chloro-3′-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone

To a stirred, cooled (0° C.) solution of 29.3 g (122 mmol) of 2′-amino-5′-chloro-3′-hydroxy-2,2,2-trifluoroacetophenone in 280 mL of DMF was added 23.8 g (350 mmol) of imidazole followed by 66 g (250 mmol) of t-butyldimethylsilyl trifluoromethanesulfonate over 10 min. The reaction was stirred 5 h at 0° C. and diluted with 800 mL of 1:1 ether-hexanes. The solution was washed twice with water and once with brine, dried (MgSO₄) and concentrated under reduced pressure to give a dark oil. The crude product was rapidly passed through an 800 g plug of silica gel (elution with hexanes followed by 6:1 hexanes-ether) to afford, after evaporation of solvent, 42.5 g (98%) of 2′-amino-5′-chloro-3′-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone as a yellow oil. The product solidified after extended evacuation at 0.01 torr to give a yellow solid, mp 45-46.5° C. ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.36(m, 1H); 6.85(d, 1H, J=2.2 Hz); 6.7-6.8(br. s, 2H); 1.03(s, 9H); 0.30(s, 6H). High resolution mass spec: calculated for C₁₄H₂₀NO₂ClF₃Si(M+H)⁺: 354.0904, found: 354.0900. Analysis calculated for C₁₄H₁₉NO₂ClF₃Si: C, 47.52; H, 5.41; N, 3.97; Cl, 10.02. Found: C, 47.71; H, 5.36; N, 3.87; Cl, 10.02.

Part E Preparation of (+/−)-2-(2-Amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-Cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol

To a stirred, cooled (0° C.) solution of 31.8 mL (300 mmol) of 5-chloro-1-pentyne in 250 mL of THF was added 252 mL (630 mmol) of 2.5 M n-BuLi in hexanes over 20 min. Over the course of the addition the internal temperature had warmed to ambient temperature, and the mixture was stirred at this temperature for 40 min. The reaction was cooled to −20° C. and treated with a solution of 32.7 g (97.4 mmol) of 2′-amino-5′-chloro-3′-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone in 50 mL of THF over 10 min. The dark solution was stirred an additional 30 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 800 mL of 0° C. 1 N citric acid with rapid stirring. The mixture was extracted twice with ether, and the combined organic extracts were washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 28.8 g (70%) of (+/−)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cycolpropyl-1,1,1-trifluoro-3-butyn-2-ol as an off-white solid, mp 125-126° C. ¹H NMR (300 MHz, CDCl₃) δ 7.22(d, 1H, J=2.2 Hz); 6.76(d, 1H, J=2.2 Hz); 4.86(br. s, 1H); 4.39(br. s, 2H); 1.32-1.43(m, 1H); 1.02(s, 9H); 0.79-0.92(m, 4H); 0.27(s, 3H); 0.26(s, 3H). High resolution mass spec: calculated for C₁₉H₂₆NO₂ClF₃Si(M+H)⁺: 420.1373, found: 420.1363.

Part F Preparation of (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled (−25° C.) solution of 28.8 g(68.6 mmol) (+/−)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol in 600 mL of toluene was added 36 mL (206 mmol) of N, N-diisopropylethylamine followed by 38.9 mL (75 mmol) of a 1.93 M solution of phosgene in toluene over 20 min. The solution was stirred an additional 20 min. at −25° C. after which time it was warmed to −5° C. and quenched with water. The mixture was washed with 100 mL of 1 N aqueous HCl then brine, dried (MgSO₄), and concentrated under reduced pressure to afford a tan solid. The crude product was dissolved in 200 mL of THF, cooled to 0° C., and treated with 40 mL of 1 M tetra-(n-butyl)ammonium fluoride in THF over 5 min. The solution was diluted with 200 mL of ether and washed sequentially with 1 M aqueous citric acid, water, and brine. The solution was dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel. Elution with 1:3 ether-hexanes then 1:1 ether-hexanes afforded, after concentration under reduced pressure, 21.4 g (94%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.46(br s, 1H); 7.01-7.07(m, 2H); 1.33-1.43(m, 1H); 0.81-0.97(m, 4H). High resolution mass spec: calculated for C₁₄H₁₀NO₃ClF₃(M+H)⁺: 332.0301, found: 332.0283.

Example 2

Preparation of (−)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Chromatography of 22 g of racemic 6-chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (I) on a Chiralpak AD-7.5 cm I.D.×30 gm column using 20% methanol-80% carbon dioxide as the mobile phase at a flow rate of 120 mL/min. gave two fractions. The faster-eluting fraction was concentrated and recrystallized from hexanes and a minimal amount of ethyl acetate to afford 5 g of the title compound as a white solid, mp 170-172° C. ¹H NMR (300 MHz, CDCl₃) δ 8.46(br s, 1H); 7.01-7.07(m, 2H); 1.33-1.43(m, 1H); 0.81-0.97(m, 4H). [α]Na_(d) (25° C.)=−32°, c=0.28. Analysis calculated for C₁₄H₉NO₃ClF₃: C, 50.70; H, 2.75; N, 4.22; Cl, 10.69. Found: C, 50.74; H, 2.86; N, 4.26; Cl, 10.77.

Example 3 Preparation of (−) 6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one by Rat Hepatic Microsomal Fractions

Incubation of (−) 6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (NNRTI) with hepatic microsomes from rats previously treated with NNRTI and cofactors required to support cytochromes P450 oxidative metabolism resulted in the formation of one major metabolite separable from NNRTI by reverse phase high performance liquid chromatography (HPLC). Incubations were conducted for 2 hours at 37° C. in a physiological buffer. After precipitating the protein with acetonitrile, the supernatants were dried under nitrogen and reconstituted in a mixture of 55:45 (v/v) acetonitrile:0.01% aqueous formic acid (pH 3.5) and injected onto the HPLC system. The column effluent was monitored at 247 nm. The single peak observed to elute at approximately 4 minutes was collected and combined from multiple injections. Final purification was accomplished using the same HPLC system and a linear gradient developed over 15 minutes starting with solvent A (50:50 (v/v) methanol:0.01% aquesous formic acid, pH 3.5) and increasing the proportion of solvent B (80:20 v/v methanol:0.01% aqueous formic acid pH 3.5), then holding solvent B constant for 5 minutes before re-equilibration with solvent A. The single, sharp peak eluting at approximately 16.5 minutes was collected and dried under vacuum.

The purified metabolite described above was dissolved in 0.2 mL of methanol-d4 and placed in a 3 mm NMR tube. The proton NMR spectrum was acquired using a 30 degree pulse, a 4 second acquisition time and a 2 second relaxation delay during which the residual water signal was suppressed by selective irradiation. The spectrum was referenced to solvent at 3.30 ppm.

Example 4

Preparation of (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A Preparation of 4′-Chloro-2′-fluoro-2,2-dimethylpropionanilide

To a stirred, cooled (0° C.) solution of 3.64 g (25.0 mmol) of 4-chloro-2-fluoroaniline and 4.2 mL (30 mmol) of triethylamine in 50 mL of THF was added 4.18 mL (26 mmol) of pivaloyl chloride. After stirring for 10 min. at 0° C. the mixture was warmed to ambient temperature and poured into 0.5N HCl. The mixture was extracted with 100 mL of ether, and the organic extract was washed sequentially with NaHCO₃ and brine. The solution was dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel (elution with 3:1 hexanes-ether) to give, after removal of solvent, 5.2 g (92%) of 4′-chloro-2′-fluoro-2,2-dimethylpropionanilide as a pale pink solid (IX), mp 70.5-71° C. ¹H NMR (300 MHz, CDCl₃) δ 8.36(t, 1H, J=8.4 Hz); 7.57(br. s, 1H); 7.10-7.17(m, 2H); 1.30(s, 9H). ¹⁹F NMR (282 MHz, CDCl₃) δ −129.8. High resolution mass spec: calculated for C₁₁H₁₄NOClF(M+H)⁺: 230.0748, found: 230.0760.

Part B Preparation of 2′-(Trimethylacetamido)-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone

To a stirred, cooled (−50° C.) solution of 0.92 g (4.0 mmol) of 4′-chloro-2′-fluoro-2,2-dimethylpropionanilide in 10 mL of THF was added 2.5 mL (4.2 mmol) of 1.7 M t-BuLi in pentane over 5 min. The solution was stirred for 5 min. and treated with 1.0 mL (8.4 mmol) of ethyl trifluoroacetate over 2 min. The reaction was warmed to ambient temperature, stirred 15 min., and quenched with 1N aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed sequentially with water then brine. The solution was dried(MgSO₄) and concentrated under reduced pressure to give an oil. The crude amide was chromatographed on silica gel (elution with 3:1 hexanes-ether followed by 1:1 hexanes-ether) to give 570 mg (43%) of 2′-(trimethylacetamido)-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone as an off-white solid. ¹H NMR(300 MHz, CDCl₃) δ 8.68(s, 1H); 7.45-7.47(m, 1H); 7.08(dd, 1H, J=9.5, 2.6 Hz); 1.3(s, 9H). High resolution mass spec: calculated for C₁₃H₁₃NO₂ClF₄(M+H)⁺: 326.0571, found: 326.0579.

Part C: Preparation of 2′-Amino-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone

A stirred solution of 0.35 g (1.07 mmol) of 2′-(trimethylacetamido)-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone in 3 mL of 1,2-dimethoxyethane and treated with 24 mL of 6N aq. HCl. The mixture was stirred at reflux for 2 h, cooled to RT, and brought to pH 9 with K₂CO₃. The mixture was extracted twice with ether and the combined organic extracts were washed with brine, dried (MgSO₄), and concentrated under reduced pressure to give 240 mg (92%) of 2′-amino-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone as an oily orange solid. ¹H NMR (300 MHz CDCl₃) δ 7.54(m, 1H); 7.25(dd, 1H, J=10.6, 2.2 Hz); 6.40-6.60(br. s, 2H). High resolution mass spec: calculated for C₈H₄NOClF₄(M⁺): 240.9918, found: 240.9914. ¹⁹F NMR (282 MHz, CDCl₃) δ −132.7(s, 1F), −70.6(s, 3F).

Part D: Preparation of (+/−)-2-Amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol

To a stirred, cooled (0° C.) solution of 2.0 mL (7.0 mmol) of 3.5 M cyclopropylacetylene in toluene was added 2 mL of THF followed by 2.8 mL (7.0 mmol) of 2.5 M n-BuLi in hexanes over 2 min. The solution was stirred in 5 min. at 0° C., warmed to RT, and stirred a further 20 min. The reaction was cooled to 0° C. and treated with a solution of 300 mg (1.24 mmol) of 2′-amino-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone in 3 mL of THF over 2 min. The solution was stirred an additional 10 min, and the cold bath was removed. The reaction was stirred 5 min and poured into 0.5 N citric acid. The mixture was extracted with ether, and the organic extract was washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 185 mg (49%) of (+/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol as an off-white solid, mp 131-135° C. ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.36(m, 1H); 7.04(dd, H, J=10.4, 2.4 Hz); 4.58(br. s. 2H); 3.82(br. s, 1H); 1.35-1.44(m, 1H); 0.80-0.99(m, 4H). ¹⁹F NMR (282 MHz, CDCl₃) δ −131.5(s, 1F), −80.5(s, 3F). High resolution mass spec: calculated for C₁₃H₁₁NOClF₄(M+H)⁺: 308.0470, found: 308.0465.

Part E: Preparation of (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred cooled (−25° C.) solution of 144 mg (0.47 mmol) of +/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 6 mL of toluene was added 0.28 mL (2.0 mmol) of triethylamine followed by 0.62 mL( 1.2 mmol) of a 1.93 M solution of phosgene in toluene over 3 min. The solution was stirred an additional 30 min. at −25° C. after which time it was warmed to ambient temperature and quenched with 0.5 N aq. citric acid. The mixture was extracted once with ether and once with ethyl acetate, and the combined organic extracts were washed sequentially with sat'd aq. NaHCO₃, water, and brine. The solution was dried (MgSO₄), and concentrated under reduced pressure to afford a tan solid. The crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether) to afford, after concentration, 90 mg (58%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.65(br s, 1H); 7.32-7.34(m, 1H); 7.22(d, 1H, J=2.2 Hz); 1.36-1.43(m, 1H); 0.82-0.98(m, 4H). ¹⁹F (282 MHz, CDCl₃) δ −132.5(s, 1F), −81.1(s, 3F). High resolution mass spec: calculated for C₁₄H₉NO₂ClF₄(M+H)⁺: 334.0258, found: 334.0244.

Example 5 Preparation of (+/−)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of 2-Amino-5-methylbenzoyl N-methoxy-methylamide

To a solution of 2-amino-5-methylbenzoic acid (7.6 g, 50.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (12.5 g, 60.4 mmol) in acetonitrile (80 mL) were added triethylamine (15.8 mL, 60.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.3 g, 55.3 mmol) and the mixture was stirred at room temperature for 5 hours. At the end of the stirring, methylene chloride (200 mL) was added and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellow syrupy residue. It was purified by column chromatography on silica gel with elution by 15:85 ethyl acetate-hexane to give pure 2-amino-5-methylbenzoyl N-methoxy-methylamide.

Part B: Preparation of 2-Amino-5-methylphenylisopropylketone

To a solution of 2-amino-5-methylbenzoyl N-methoxy-methylamide (472.6 mg, 2.4 mmol) in dry THF (3 mL) at −20° C. were added diisopropylethylamine (0.84 mL, 4.8 mmol) and chlorotrimethylsilane (0.61 mL, 4.8 mmol) dropwise and the mixture was stirred for 1 hour at −20˜5° C. It was then cooled to −20° C. again and was added 2M-isopropyl magnesium chloride in THF (4.8 mL, 9.6 mmol) dropwise. The mixture was stirred for 1.5 hours at −20˜10° C. After cooling to 0° C. was added saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with 1N-HCl, water, saturated sodium bicarbonate and water, and dried over anhydrous sodium sulfate. It was evaporated in vacuo to give an oily residue. Column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane afforded pure 2-amino-5-methylphenylisopropylketone (201 mg) as an oil.

Part C: Preparation of 2-Amino-5-methyl-α-cyclopropylethynyl-α-isopropyl-benzyl alcohol

To a solution of cyclopropylacetylene (105 mg, 1.59 mmol) in THF (3 mL) at −20° C. was added 1.6M-nBuLi in hexane (0.96 mL, 1.54 mmol) dropwise and the mixture was stirred at the same temperature for 0.5 hours. Then a solution of 2-amino-5-methylphenylisopropylketone (94.5 mg, 0.53 mmol) in THF (3 mL) was added and the mixture was stirred for 5 hours at −20˜20° C. The reaction was quenched with saturated NH₄Cl and the product was extraxted with ethyl acetate. After washing with brine, the extract was dried over anhydrous sodium sulfate and evaporated to give the crude amino-alcohol as an oil.

Part D: Preparation of 4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude amino-alcohol (0.53 mmol) in dry toluene (5 mL) at −20° C. were added diisopropylethylamine (0.29 mL, 1.89 mmol) and 0.31 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1 hour at −20˜0° C. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na₂SO₄ and evaporated in vacuo to give an oily residue. Column chromatography on silica gel (2:8 EtOAc-hexane) provided pure titled compound (38 mg).

Example 6 Preparation of (+/−)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of 2-Iodo-4-methylaniline

To a stirred solution of p-toluidine (5 g, 46.7 mmol) in methylene chloride (25 mL) was added a solution of sodium bicarbonate (4.7 g, 56 mmol) in water (75 mL). Then was added iodine (11.26 g, 44.33 mmol) in small portions and the mixture was stirred for 16 hours at room temperature. The reaction was quenched with saturated NaHSO₃ and the product was extracted with methylene chloride. The methylene chloride layer was washed with brine, dried over Na₂SO₄, and evaporated in vacuo to give a crude 2-iodo-4-methylaniline.

Part B: Preparation of Trimethylacetyl 2-Iodo-4-methylanilide

To a stirred mixture of 2-iodo-4-methylaniline (46.7 mmol) in chloroform (50 mL) and 50 mL of saturated sodium carbonate was added trimethylacetyl chloride dropwise over a period of 15 minutes and the mixture was stirred vigorously for 45 minutes at room temperature. The product was extracted with chloroform, washed with water and dried over Na₂SO₄. Evaporation of the solvent in vacuo afforded the pivaloyl amide as a solid. It was recrystallized from ethyl acetate and hexane.

Part C: Preparation of Trimethylacetyl 4-methyl-2-trifluoroacetylanilide

To a stirred solution of trimethylacetyl 2-iodo-4-methylanilide (10.7 g, 33.75 mmol) in 50 mL of dry THF at −78° C. was added 1.6M-BuLi in hexane (48.5 mL, 77.6 mmol) dropwise and the mixture was stirred for an hour at the same temperature. Then ethyl trifluoroacetate (9.6 mL, 81 mmol) was added dropwise and the mixture was stirred for 0.5 hours at −78° C. At the end of the stirring saturated NH₄Cl solution was added and the mixture was warmed up to room temperature. The product was extracted with ethyl acetate, washed with water and brine, and dried over Na₂SO₄. The solution was concentrated and the residue was column chromatographed on silica gel (1:9 EtOAc-hexane) to give the desired trimethylacetyl 4-methyl-2-trifluoroacetylanilide (1.29 g, 13% yield) and trimethylacetyl 4-methylanilide (major product).

Part D: Preparation of 4-Methyl-2-trifluoroacetylaniline.

To a solution of trimethylacetyl 4-methyl-2-trifluoroacetylanilide (1.29 g) in 10 mL of dimethoxyethane was added 6N-HCl (15 mL) and the mixture was refluxed for 2.5 hours with stirring. After cooling it was poured over ice and was made basic with saturated NaHCO₃. The product was extracted with ethyl acetate, washed with brine, and dried over Na₂SO₄. Evaporation of the solvent provided the aniline as a yellow solid in near quantitative yield.

Part E: Preparation of 2-Amino-5-methyl-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

To stirred solution of 3-methyl-1-butyne (0.26 mL, 2.59 mmol) in 5 mL of dry THF at −20° C. was added 1.6M-BuLi in hexane (1.4 mL, 2.24 mmol) dropwise and the mixture was warmed up to 0° C. over a period of 1 hour with stirring. It was the cooled back to 20° C. and was added dropwise a solution of 4-methyl-2-trifluoroacetylaniline (150 mg, 0.74 mmol) in 2 mL of THF. After stirring for an hour at −20˜0° C. was added saturated NH₄Cl (˜5 mL), and the product was extracted with ethyl acetate, washed with brine and dried over Na₂SO₄. The solvents were evaporated off to give crude amino-alcohol as a yellow solid residue.

Part F: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude amino-alcohol (0.74 mmol) in dry toluene (7.5 mL) at −20° C. were added diisopropylethylamine (0.39 mL, 2.22 mmol) and 0.42 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1 hour at −20˜0° C. After solution of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na₂SO₄ and evaporated in vacuo to give an oily residue. Column chromatography on silica gel (2:8 EtOAc-hexane) and recrystallization (EtOAc and hexane) provided pure titled compound (61 mg, 28% yield for 2 steps) as white crystals, mp 198-199° C.

Example 7 Preparation of (+/−)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of 4-Amino-3-iodo-acetophenone

To a solution of 4-aminoacetophenone (5 g, 37 mmol) in 15 mL of CH₂Cl₂ and 75 mL of water was added sodium bicarbonate (3.73 g, 44.4 mmol) followed by iodine (8.92 g, 35.1 mmol), and the mixture was stirred for 5 hours at room temperature. The reaction was quenched by portionwise addition of sodium bisulfite until the iodine color disappeared. The product was extracted with CH₂Cl₂, washed with water, dried over Na₂SO₄. Evaporation of the solvent gave crude 4-amino-3-iodo-acetophenone as solid (7.92 g).

Part B: Preparation of Trimethylacetyl 2-iodo-4-acetylanilide

To a stirred mixture of 4-amino-3-iodo-acetophenone (7.92 g, 30.3 mmol) in chloroform (50 mL) and 50 mL of saturated sodium carbonate was added trimethylacetyl chloride (7.8 mL, 63.7 mmol) dropwise over a period of 15 minutes and the mixture was stirred vigorously for 16 hours at room temperature. The product was extracted with chloroform, washed with water and dried over Na₂SO₄. Evaporation of the solvent in vacuo affored the pivaloyl amide as a brown oil. It was column chromatographed (silica gel, 1:9 EtOAc-hexane) to afford pure trimethylacetyl 2-iodo-4-acetylanilide (5.83 g) as white crystals.

Part C: Preparation of Trimethylacetyl 2-iodo-4-(2-methyl-1,3-dithian-2-yl)anilide.

To a stirred solution of trimethylacetyl 2-iodo-4-acetylanilide (2.9 g, 8.45 mmol) and 1,3-propanedithiol in 25 mL of THF at 0° C. was added borontrifluorate etherate (0.63 mL, 5.1 mmol) and the mixture was stirred for 16 hours at room temperature. Then was added second portion of borontrifluorate etherate (0.63 mL, 5.1 mmol) and it was continued to stir for 44 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water saturated NaHCO3 and brine, dried over MgSO4 and evaporated to a clear oil. It was column chromatographed (silica gel, 5:95 EtOAc-hexane) to give pure thioaketal as a foamy solid (2.85 g).

Part D: Preparation of Trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide

To a stirred solution of trimethylacetyl 2-iodo-4-(2-methyl-1,3-dithian-2-yl)anilide (2.29 g, 5.26 mmol) in 20 mL of dry THF at −78° C. was added 1.6M-nBuLi in hexane (6.7 mL, 10.7 mmol) dropwise and the mixture was stirred for 45 minutes at the same temperature. Then ethyl trifluoroacetate (12.6 mL, 105.2 mmol) was added dropwise and the mixture was gradually warmed up to room temperature over a period of 3 hours. At the end of the stirring saturated NH₄Cl solution was added, and the product was extracted with ethyl acetate, washed with water and brine, and dried over Na₂SO₄. The solution was concentrated and the residue was column chromatographed on silica gel (1:9 EtOAc-hexane) to give the desired trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide (0.63 g) and trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)anilide (1.33 g).

Part E: Preparation of 4-(2-Methyl-1,3-dithian-2-yl)-2-trifluoroacetylaniline

To a solution of trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide (0.63 g) in 10 mL of methanol was added 6N-HCl (2 mL) and the mixture was refluxed for 4 hours with stirring. After cooling it was poured over ice and was made basic with saturated NaCHO₃. The product was extracted with ethyl acetate, washed with brine, and dried over Na₂SO₄. Evaporation of the solvent provided the desired 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylaniline as a bright yellow solid.

Part F: Preparation of 2-Amino-5-(2-methyl-1,3-dithian-2-yl)-α-cyclopropylethynyl-α-trifluoromethyl-benzyl alcohol

To stirred solution of cyclopropylacetylene (122 mg, 1.9 mmol) in 5 mL of dry THF at −20° C. was added 1.6M-nBuLi in hexane (0.99 mL, 1.59 mmol) dropwise and the mixture was warmed up to 0° C. over a period of 45 minutes with stirring. It was the cooled back to −20° C. and was added dropwise a solution of 4-methyl-2-trifluoroacetylaniline (150 mg, 0.74 mmol) in 2 mL of THF. After stirring for 1.5 hours at −20˜0° C. was added saturated NH₄Cl (˜5 mL), and the product was extracted with ethyl acetate, washed with brine and dried over Na₂SO₄. The solvents were evaporated off to give crude amino-alcohol as a bright yellow solid residue.

Part G: Preparation of 4-Cyclopropylethynyl-4-trifluoromethyl-6-(2-methyl-1,3-dithian-2-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude amino-alcohol (0.53 mmol) in dry toluene (5 mL) at −20° C. were added diisopropylethylamine (0.28 mL, 1.59 mmol) and 0.3 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1.5 hours at −20˜0° C. and for 5 minutes at room temperature. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na₂SO₄ and evaporated in vacuo to give an oily residue. It was purified by preparative TLC on a silica gel plate (3:7 EtOAc-hexane) to give pure titled compound (77 mg).

Part H: Preparation of 6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred solution of 4-cyclopropylethynyl-4-trifluoromethyl-6-(2-methyl-1,3-dithian-2-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (64 mg, 0.154 mmol) in 5 mL of methanol and 0.5 mL of water were added mercuric chloride (92 mg, 0.339 mmol) and mercuric oxide (50 mg, 0.23 mmol), and the mixture was refluxed for 2 hours. After cooling it was filtered through Celite and rinsed with EtOAc. The filtrate was washed with water and brine, dried over MgSO₄, and evaporated to give an oily residue. Column chromatography (silica gel, 2:8 EtOAc-hexane) afforded pure 6-6cetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Example 8 Preparation of (+/−)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of 2,3-Difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butynyl-α-trifluoromethyl-benzyl alcohol

To a solution of 3-methyl-1-butyne (0.73 g, 10.7 mmol) in dry THF (5 mL) at −20° C. was added 1.6M-nBuLi in hexane dropwise and the mixture was stirred for 15 minutes at the same temperature. Then a solution of 2,3-diflupro-6-triphenylmethylamino-α,α,α-trifluoroacetophenone (1 g, 2.14 mmol) in 5 mL or THF was added dropwise at −20° C. After stirring for 10 minutes, the cooling bath was removed and it was allowed to warm up to room temperature. The mixture was stirred for 45 minutes and was poured into saturated NH₄Cl. The product was extracted with ether, washed with saturated NaHCO₃ and brine and dried over MgSO₄. Evaporation of solvent gave an oily residue, which was crystallized from methanol, ether and hexane mixture to provide pure product (0.432 g, 37.6%).

Part B: Preparation of 2,3-Difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol

To a solution of 2,3-difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butynyl-α-trifluoromethyl-benzyl alcohol (0.431 g, 0.8 mmol) in 5 mL of dry THF was added 1M-lithium aluminumhydride in THF (2.41 mL, 2.41 mmol) at room temperature and the mixture was stirred for 1 hour. The reaction was quenched with several drops of saturated NH₄Cl and was added about 20 mL of ether. After stirring for 10 minutes it was washed with saturated NaHCO3 and dried over MgSO4. Evaporation of the solvent gave the desired transolefinic compound in near quantitative yield.

Part C: Preparation of 6-Amino-2,3-Difluoro-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol

A solution of the crude product of step 2 (0.8 mmol) and 1.33 mL of c-HCl in methanol (5 mL) was stirred for 1 hour at room temperature and basified with saturated NaHCO3. It was extracted with ether and washed with brine. After drying over MgSO4, the solvent was evaporated off to give an oily residue. It was crystallized from hexane to give pure 6-amino-2,3-Difluoro-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol (0.184 g, 78%).

Part D: Preparation of 5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude amino-alcohol (0.13 g, 0.44 mmol) in dry toluene (5 mL) at 0° C. were added diisopropylethylamine (0.23 mL, 1.32 mmol) and 0.24 mL of 2M-phosgene in toluene (0.48 mmol) dropwise and the mixture was stirred for 5 minutes at 0° C. and for 30 minutes at room temperature. After addition of saturated NH₄Cl (5 mL) it was extracted with ether and the organic layer was washed with brine. It was dried over MgSO₄ and evaporated in vacuo to give an oily residue. It was purified by column chromatography on Silica gel (1:9 ether-hexane) to give pure titled compound (0.051 g, 36%).

Example 9 Preparation of (+/−)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of N-trimethylacetyl-3,4-difluoroanilide

To a solution of 3,4-difluoroaniline (19 mL, 191 mmol) in methylene chloride (500 mL) at 0° C. was added triethylamine (32 mL, 230 mmol) followed dropwise with trimethylacetyl chloride (24 mL, 191 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was poured onto 3N HCl and extracted with methylene chloride (3×100 mL) and the combined organic extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. The residue was taken up in hexanes (300 mL) and filtered through a sintered glass funnel. The solids are washed thoroughly with hexanes (500 mL) and dried under vacuum to give 37.36 g of the pivaloyl amide as a solid (40.68 g theoretical, 92% yield).

Part B: Preparation of N-Trimethylacetyl 5,6-difluoro-2-trifluoroacetylanilide

To a solution of N-trimethylacetyl-3,4-difluoroanilide (4.0 g, 14.6 mmol) in THF (60 mL) at −78° C. was added dropwise 1.6M-nBuLi in hexane (22 mL, 35 mmol) and the resulting reaction mixture was allowed to stir at −78° C. for 1 h. The Ethyl trifluoroacetate (4 mL, 33.6 mmol) is added to the reaction mixture and the resulting solution was allowed to stir with warming to room temperature (ice bath removed after the addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part C: Preparation of 5,6-Difluoro-2-trifluoroacetylaniline

To a solution of the orange oil in DME (15 mL) was added 6N HCl (75 mL) and the resulting mixture was allowed to reflux for 2 h. The reaction mixture was cooled, made basic with solid Na₂CO₃ and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 2110 mg of 5,6-Difluoro-2-trifluoroacetylaniline as a yellow solid (3285 mg theoretical, 64% yield).

Part D: Preparation of 2-Amino-5,6-Difluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

To a solution of 3-methyl-1-butyne (0.36 mL, 3.56 mmol) in THF (6 mL) at 0° C. was added 1.6M-nBuLi in hexane (2.2 mL, 3.56 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 5,6-Difluoro-2-trifluoroacetylaniline (200 mg, 0.89 mmol) in THF (6 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part E: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of amino-alcohol (crude product, 1.21 mmol) in toluene (1 mL) at 0° C. was added N,N-diisopropylethylamine (0.54 mL, 3.12 mmol) followed by a solution of 1.93M phosgene in toluene (0.6 mL, 1.16 mmol) and the resulting solution was allowed to stir at 0° C. for 0.1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined other extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 45 mg of the title compound (284 mg theoretical, 16% yield).

Example 10 Preparation of 2-Trifluoroacetylaniline Part A: Preparation of 2-Amino-α-trifluoromethyl-benzyl alcohol

To a solution of amino ketone (155 mg, 0.7 mmol) in methanol (2 mL) at room temperature was added Pd(OH)₂ (20 mg) and hydrogenated (H₂/balloon) for 2 h. The reaction mixture was filtered through Celite and concentrated in vacuo. The solids were triturated with ether (20 mL) and dried in vacuo to give 117 mg of 2-Amino-α-trifluoromethyl-benzyl alcohol as a pale yellow solid. (134 mg theoretical, 87% yield).

Part B: Preparation of 2-Trifluoroacetylaniline

To a slurry of amino alcohol (520 mg, 2.72 mmol) in methylene chloride (5 mL) at room temperature was added MnO₂ (10xwt, 5 g) and the resulting reaction mixture was allowed to stir at room temperature for 0.75 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give an orange oil which is used without further purification due to instability of compound.

Example 11 Preparation of 3-Fluoro-2-trifluoroacetyltriphenylmethylaniline Part A: Preparation of 2-Amino-6-fluorobenzoyl N-methoxy-methylamide

To a solution of 2-amino-6-fluorobenzoic acid (5 g, 32.26 mmol) in AcCN (100 mL) at room temperature was added N,O-dimethylhydroxylamine hydrochloride (3.8 g, 38.71 mmol), EDAC (7.4 g, 38.71 mmol), followed by triethylamine (5.38 mL, 38.71 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 6 h. The reaction mixture was poured onto saturated NaHCO₃ and extracted with EtOAc (3×100 mL). The combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 25% EtOAc-hexanes eluant) provided 4.29 g of the desired compound (5.87 g theoretical, 73% yield).

Part B: Preparation of 2-Triphenylmethylamino-6-fluorobenzoyl N-Methoxy-methylamide

To a solution of 2-amino-6-fluorobenzoyl N-methoxy-methylamide (300 mg, 2.14 mmol) in methylene chloride (10 mL) at room temperature was added N,N′-diisopropylamine (1.2 mL, 6.4 mmol) followed by triphenylmethyl bromide (830 mg, 2.57 mmol) and the resulting reaction mixture is allowed to stir at room temperature for 0.5 h. The reaction mixture was poured onto water and extracted with methylene chloride (3×50 mL) and the combined organic extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes) provided 832 mg of the desired compound (942 mg theoretical, 88% yield).

Part C: Preparation of 2-Triphenylmethylamino-6-fluorobenzaldehyde

To a solution of 2-triphenylmethylamino-6-fluorobenzoyl N-methoxy-methylamide (300 mg, 0.68 mmol) in THF (4 mL) at −78° C. was added lithium aluminum hydride (30 mg, 0.82 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (dry ice bath removed after addition of reagent) for 1 h. The reaction mixture was quenched with 20% KHSO₄ and extracted with EtOAc (3×100 mL) and the combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 5% EtOAc-hexanes) provided 182 mg of the title compound (260 mg theoretical, 70% yield).

Part D: Preparation of 2-Amino-6-fluoro-α-trifluoromethylbenzyl Alcohol

To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2 mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes) provided 88 mg of the title compound (108 mg theoretical, 82% yield).

Part E: Preparation of 3-Fluoro-2-trifluoroacetyltriphenylmethylaniline

To a solution of 2-amino-6-fluoro-α-trifluoromethyl-benzyl alcohol (88 mg, 0.2 mmol) in methylene chloride (6 mL) at room temperature was added manganese(IV)oxide (900 mg, 10×wt) and the resulting reaction mixture was allowed to stir at room temperature for 5 h. The reaction mixture is filtered through Celite and concentrated in vacuo. Chromatography (SiO₂, 5% EtOAc-hexanes) provided 52 mg of the title compound (90 mg theoretical, 58% yield).

Example 12 Preparation of (±)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of 5-(t-Butoxycarbonylamino)-2-chloropyridine

To a stirred solution of 2.83 g(22.0 mmol) of 5-amino-2-chloropyridine in 20 mL of anhydrous THF was added 44.0 mL(44.0 mmol) of a 1.0M solution of NaHMDS in toluene over 5 min. The dark solution was stirred 15 min. and 4.36 g(20 mmol) of di-t-butyldicarbonate in 5 mL of THF was introduced over 2 min. The thick mixture was stirred an additional 1 h and poured into 0.5N aq. HCl. The solution was extracted with ethyl acetate, and the organic extract was washed with saturated aq. NaHCO₃, water, and brine. The solution was dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel(gradient elution with 3:1 hexanes-ether then ether) to give, after evaporation of solvents, 3.81 g(83%) of 5-(t-butoxycarbonylamino)-2-chloropyridine as a white solid, mp 122-123° C. ¹H NMR(300 MHz, CDCl₃) δ 8.23(d, 1H, J=2 Hz); 7.98(br. d, 1H, J=8 Hz); 7.25(d, 1H, J=8 Hz); 6.58(s, 1H); 1.52(s, 9H).

Part B: Preparation of 2-(5-(t-Butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol

To a stirred, cooled (−50° C.) solution of 643 mg(2.8 mmol) of 5-(t-butoxycarbonylamino)-2-chloropyridine in 8 mL of anhydrous THF was added 4.7 mL(7.9 mmol) of t-BuLi in pentane over 3 min. The solution was stirred an additional 35 min. at −50° C. after which time 1 mL(large excess) of 4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-one. The solution was stirred an additional 20 min., warming to ambient temperature. The reaction was poured into 10% aq. citric acid, and the mixture was extracted with 1:1 ether-ethyl acetate. The organic extract was washed with saturated aq. NaHCO₃, then brine, dried (MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel(gradient elution with 6:1 then 3:1 hexanes-ethyl acetate) afforded, after removal of solvent, 620 mg(56%) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an amorphous solid. Mass spec.(NH₃—CI): 391((M+H)⁺, 100%); 291((M+H-t-Boc)⁺, 49%). ¹H NMR(300 MHz, CDCl₃) δ 9.08(br. s, 1H); 8.29(br. s, 1H); 7.59(s, 1H); 1.50(s, 9H); 1.37-1.43(m, 1H); 0.81-0.97(m, 4H).

Part C: Preparation of 4-Cyclopropylethynyl-6-chloro-4 Trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred solution of 230 mg(0.59 mmol) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol in 6 mL of anhydrous toluene was added 0.92 mL of a 2.5M solution of n-BuLi in hexanes. The solution was brought to reflux and stirred 10 min. after which time an additional 0.10 mL of n-BuLi was added. The solution was stirred an additional 20 min. at reflux and cooled to ambient temperature. The reaction was poured into 10% aq. citric acid and extracted with ether. The organic extract was washed with brine, dried(MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel(elution with 3:1 hexanes-ethyl acetate) afforded 25 mg (13%) of 4-cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4dihydro-2H-3,1-benzoxazin-2-one as an amorphous solid. Mass spec.(NH₃—CI): 334((M+NH₄)⁺, 100%); 317((M+H)⁺, 100%); 273((M+H—CO₂)⁺, 21%). ¹H NMR(300 MHz, CDCl₃) δ 9.62(br. s, 1H); 8.17(s, 1H); 7.44(s, 1H); 1.36-1.44(m, 1H); 0.82-0.99(m, 4H).

Example 13 Preparation of (±)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of 4-Chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, gently refluxing solution of 7.0 g(31.9 mmol) of 2-amino-5-methoxy-(1′,1′,1′-trifluoro)acetophenone in 27 mL of anhydrous toluene was added 24.8 mL(47.9 mmol) of a 1.93M solution of phosgene in toluene over 2 min.(Note: A dry ice-acetone cold finger is used to condense phosgene during this reaction.). The solution is warmed at reflux for 2 h, cooled, and charged with 15 mL of hexanes. Upon stirring overnight at ambient temperature a precipitate formed which was filtered, washed with hexanes, and briefly air-dried to give 5.06 g(60%) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid mp 112-114° C. ¹H NMR(300 MHz, CDCl₃) δ 9.05(br. s, 1H); 7.07(br. s, 1H); 7.02(dd, 1H, J=8, 2 Hz); 6.90(d, 1H, J=8 Hz); 3.83(s, 3H).

Part B: Preparation of 6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of 0.15 mL of 2-methoxyethanol in 5 mL of anhydrous THF at ambient temperature was added 20 mg of 100% sodium hydride. After 20 min. 100 mg of 4,6-dichloro-4-(trifluoromethyl)benzoxazinone was added, and the resulting solution was stirred at ambient temperature for 30 min. The reaction mixture was poured onto aqueous ammonium chloride and was extracted with ethyl acetate. The organic extracts were washed with brine, dried and evaporated. The crude product was purified by preparative TLC on silica gel (elution with ethyl acetate/hexanes 1:1) to afford a material which was crystallized from ethyl acetate-hexanes to afford 81 mg (71%) of the title compound.

Example 14 Preparation of (±)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of 230 mg of 4,6-dichloro-4(trifluoromethyl)benzoxazinone in 20 mL of dry ether was added 0.250 mL of n-propylamine. After stirring 30 min at ambient temperature, the solution was partitioned between ether and water, and the organic layer was washed with brine, dried, and evaporated. The crude product was purified by column chromatography on silica gel (elution with ethyl acetate-hexanes 1:3) to afford after crystallization from hexanes 24 mg (9.7%) of the title compound.

Example 15 Preparation of (±)-6-Chloro-4-[2-(furan-2-yl)ethynyl]-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of 5.9 g (25 mmoles) of 1,1-dibromo-2-(furan-2-yl)ethylene in 124 mL of anhydrous THF at −20° was added dropwise 31.0 mL of 1.6 M n-butyllithium in hexanes (50 mmoles). This solution was allowed to warm to ambient temperature over a period of 30 min, after which time it was cooled to −50°. 4,6-Dichloro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one (2.65 g, 9.27 mmoles) was added in one portion, and the resulting solution was allowed to warm to −35° over 40 min. The reaction was quenched by the addition of aqueous ammonium chloride, and this mixture was poured onto water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (elution with 15% and 30% ethyl acetate in hexanes) affording 3.5 g of a solid which was recrystallized from ethyl acetate/hexanes to afford 3.03 g (95.7%) of the title compound.

Example 16 Preparation of (±)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled (−78° C.) solution of 0.5 g(excess) of 1-butyne in 3 mL of anhydrous THF was added 1.6 mL(4.0 mmol) of a 2.5M solution of n-BuLi in hexanes over 3 min. The solution was stirred 5 min. and charged with 266 mg(1.00 mmol) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a single portion. The solution was warmed to −10° C. over 20 min., whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO₃ then brine. The solution was concentrated under reduced pressure, and the crude product was recrystallized from ethyl acetate-hexanes to afford 144 mg(48%) of 4-(1-butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 161-162° C. ¹H NMR(300 MHz, CDCl₃) δ 8.81(br. s, 1H); 7.07(d, 1H, J=2 Hz); 6.94(dd, 1H, J=9, 2 Hz); 6.81(d, 1H, J=8 Hz); 3.82(s, 3H); 2.34(q, 2H, J=7 Hz); 1.22(t, 3H, J=7 Hz).

Example 17 Preparation of (±)-4-(1′-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of Methyl 1-Hydroxy-1-cyclopropanecarboxylate

1-Hydroxy-1-cyclopropanecarboxylic acid (587 mg, 5.75 mmol) was dissolved in methanol (20 mL) under nitrogen. Thionyl chloride (4 drops) were added and the reaction was stirred overnight at room temperature. Triethylamine was then added until the reaction was alkaline as judged by moistened pH paper. The solvent was then removed on the rotary evaporator.

Part B: Preparation of Methyl 1-Triisopropylsilylhydroxy-1-cyclopropanecarboxylate

The residue was then dissolved in dry methylene chloride (20 mL) under a nitrogen atmosphere. Dry 2,6-lutidine (distilled from calcium hydride, 1.0 mL, 8.62 mmol) was added and the reaction cooled to 0° C. Triisopropylsilyl trifluoromethanesulfonate (2.3 mL, 8.62 mmol) was then added dropwise and stirring continued for 1 hour. The reaction was then poured into 1 N HCl and extracted with hexanes. The organic layer was washed successively with water and brine, then dried with magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography (silica) using 19:1 hexanes/ethyl acetate. This provided the silyl methyl ester in 87% yield for two steps (1.35 g).

Part C: Preparation of 1-Triisopropylsilylhydroxy-1-cyclopropanemethanol

The silyl methyl ester (1.05 g, 3.86 mmol) was dissolved in hexane (12 mL) under nitrogen. The reaction was cooled in a dry ice/acetone bath and a solution of diisobutylaluminum hydride (1.5 M in toluene, 6.4 mL, 9.64 mmol) was introduced dropwise. Stirring was continued for 2 hours when the reaction was quenched by the addition of methanol (12 mL). The reaction was warmed to room temperature and poured into a saturated aqueous solution of sodium potassium tartrate. The clarified solution was extracted with ether and the organic layer washed with water and brine. After drying over magnesium sulfate, the product was isolated by filtration and evaporation (894.4 mg, 95%). This material was of sufficient purity for direct use in the next step.

Part D: Preparation of 1-Triisopropylsilylhydroxy-1-cyclopropanecarboxaldehyde

A 100 mL flask was flame-dried and sealed under nitrogen. The flask was charged with dry methylene chloride (11 mL) and oxalyl chloride (0.44 mL, 5.07 mmol). The solution was cooled in a dry ice/acetone bath and dimethylsulfoxide was introduced (0.73 mL, 10.3 mmol). After stirring for 5 minutes, the starting material (1.065 g, 4.36 mmol) was added as a solution in methylene cholride (5.0 mL). After stirring for 20 minutes, triethylamine (3.1 mL, 22.4 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was then poured into 1 N HCl and extracted with ether. The organic layer was washed twice with water and once with brine. Drying with magnesium sulfate, filtration and evaporation then provided the crude product. This material was of sufficient purity for use in the next step.

Part E: Preparation of 1-Triisopropylsilylhydroxy-1-(2′,2′-dibromoethene)cyclopropane

A 500 mL flask was charged with carbon tetrabromide (2.89 g, 8.72 mmol) dissolved in dry methylene chloride (87 mL). The solution was cooled to −20° C. when triphenylphosphine (recrystallized from hexanes, 2.28 g, 8.72 mmol) was added and stirring continued for 45 minutes. The reaction was then cooled to −60° C. where the crude aldehyde (maximum of 4.36 mmol) dissolved in dry methylene chloride (40 mL) containing triethylamine (0.61 mL, 4.26 mmol) was added. Stirring was continued overnight with warming to room temperature. The reaction was then diluted with hexanes (1 l) and filtered through a pad of magnesium sulfate. Evaporation and purification by flash column chromatography (silica, hexanes) gave the desired dibromoolefin (35%, 607.1 mg).

Part F: Preparation of (±)-4-(1′-Triisopropylsilylhydroxy)cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

A 50 mL two-necked flasked was flame-dried in vacuo and sealed under nitrogen. The dibromoolefin was dissolved in dry tetrahydrofuran (8.0 mL) and transferred to the reaction flask. The reaction was cooled to −78° C. and a solution of n-butyllithium (2.5 M in hexanes, 1.2 mL, 2.96 mmol) was added dropwise. Stirring was continued for 20 minutes when a solution of the chlorobenzoxazinone (212 mg. 0.74 mmol) in dry tetrahydrofuran (2.0 mL) was added. The reaction was warmed to −60° C. and stirring continued for 30 minutes. The reaction was then poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine and then dried over magnesium sulfate. The crude product was isolated by filtration and evaporation. Flash chromatography (silica, 4:1 hexanes/ethyl acetate) gave the partially purified product (235 mg). A subsequent chromatography under similar conditions gave the desired material (35%, 118 mg) with suitable purity for the next step.

Part G: Preparation of 4-(1′-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

The starting material (53.0 mg, 0.117 mmol) was dissolved in dry tetrahydrofuran (2.0 mL) under nitrogen. A solution of tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 0.12 mL, 0.12 mmol) was added and stirring continued for 15 minutes. The reaction was then diluted with 1:1 hexanes/ethyl acetate and washed twice with water and once with brine. Drying with magnesium sulfate, filtration, and evaporation gave the crude product. The compound was purified by flash chromatography (silica, 4:1 hexanes/ethyl acetate to 2:1 hexanes/ethyl acetate). The desired product was isolated in 74% yield (28.7 mg). m.p. 192-194° C. HRMS: calculated for C₁₄H₁₀ClF₃NO₃, M+H): 332.0301; found 332.0296.

Example 18 Preparation of (±)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of 2-Triphenylmethylamino-5-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl Alcohol

To a solution of 3-methyl-1-butyne (0.16 mL, 1.51 mmol) in THF (2 mL) at 0° C. was added 1.6M nBuLi in hexane (0.84 mL, 1.34 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 5-fluoro-2-trifluoroacetyl-triphenylmethylaniline (300 mg, 0.67 mmol) in THF (2 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. The reaction mixture was poured onto saturated NH₄Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part B: Preparation of 2-Amino-5-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl Alcohol

To a solution of the benzyl alcohol (crude product, approx. 0.67 mmol) in methanol (5 mL) at room temperature was added concentrated hydrochloric acid (0.1 mL) and the resulting reaction mixture was allowed to stir at room temperature for 0.25 h. The reaction mixture was quenched with saturated NaHCO₃ and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 15% EtOAc-hexanes eluant) provided 103 mg of the title compound (184 mg theoretical, 56% yield over two steps).

Part C: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of amino-alcohol (103 mg 0.37 mmol) in toluene (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.30 mmol) followed by a solution of 1.93M phosgene in toluene (0.25 mL, 0.48 mmol) and the resulting solution was allowed to stir at 0° C. for 0.1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 89 mg of the title compound (111 mg theoretical, 80% yield).

Example 19 Preparation of 4-Chloro-2-cyclopropylacetylaniline

Cyclopropyllithium was prepared by the procedure of Dakkouri (Chem. Ber. 1979, 112, 3523.). To a 3 neck 100 ml flask equipped with a magnetic stir bar, a thermocouple probe, a West condenser and a nitrogen line was charged 1.0 g (0.14 mol.) of freshly cleaned Li ribbon and 20 ml anhydrous ether. The mixture was cooled to 0° C. and 5.6 ml of cyclopropylbromide (70 mmol) in 10 ml of anhydrous ether was added dropwise. The bromide solution was added over 45 min. due to the exothermic nature of the metalation reaction. After the addition was complete the lithium reagent was aged for 30 min. then cooled to −65° C. A solution of 5.53 g (28 mmol.) of 5-chloroisatoic anhydride in 80 ml THF was prepared in a dry 3 neck flask and cooled to −40° C. The cyclopropyllithium solution was transfered via canula into the anhydride solution over 30 min. The resulting milky solution was aged for 1 h at −40° C. during which time the solution became clear with a pale green color. The anion solution was quenched by addition of 1 M citric acid solution and then warmed to ambient temperature. The phases were separated and the organic layer washed with water and concentrated to provide a tacky yellow solid which was chromatographed on silica gel with ethyl acetate/hexanes (3:1) to provide 3.56 g of the title compound in 65% yield. Crystallization from heptane provides the title compound as a pale yellow solid: m.p. 73.7° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=1.5 Hz, 1 H), 7.22 (dd, J=2.3, 8.7 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 6.13 (brs, 2H), 2.56 (m, 1 H),. 1.18 (m, 2 H), 1.00 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ 201.16, 148.23, 133.83, 130.41, 121.70, 119.69, 118.56, 17.37, 11.08; IR (cm⁻¹) 3315, 3012, 1628, 1582, 1533, 1481, 1464, 1414, 1389, 1343, 1313, 1217, 1183, 1158, 1082, 1053, 1032, 985, 893, 868, 813.

Example 20 Preparation of 4-Chloro-2-((cyclopropylenthynyl)acetyl)aniline

To a 3 neck 100 ml flask equipped with a magnetic stir bar, a thermocouple probe, a solid addition funnel and a nitrogen line was charged 3.7 g (56.0 mmol.) of cyclopropylacetylene and 30 ml of anhydrous THF. The solution was cooled to −60° C. and 30 ml (53.1 mmol.) of 1.8 M hexyllithium in hexanes was added dropwise while maintaining the internal temperature below −20° C. The solution was aged at −40° C. for 30 min. and then 5 g (25.3 mmol.) of 5-chloroisatoic anhydride was added as a solid in small portions. The resulting solution was aged for 2 h at −40° C. during which time the solution became clear with a pale yellow color. The anion solution was quenched by addition of 1 M citric acid solution and then warmed to ambient temperature. The phases were separated and the organic layer washed with water and concentrated to provide a an orange solid. The product was triturated with heptanes to provides 9 as a tan solid: ¹H NMR (300 MHz, CDCl₃) δ 8.43 (m, 1 H), 8.02 (m, 1H), 7.36 (m, 1H), 1.48 (m, 1 H),. 0.99 (m, 2 H), 0.87 (m, 2 H); IR (cm⁻¹) 2978, 2221, 1641, 1579, 1502, 1434, 1410, 1370, 1299, 1055, 906, 829, 731.

Example 21 Preparation of (S)-6-Chloro-4-(chloro)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a 3 neck flask equipped with a magnetic stirrer, a thermocouple probe and a dry ice condenser was charged 25 g (0.11 mol.) of trifluoroketone 3 and 150 ml of anhydrous toluene. This yellow solution was then heated to gentle reflux and a solution (87 ml, 0.17 mol.) of phosgene (1.93 M) in toluene was added subsurface. The solution was heated to reflux (temperature range at 104 to 110° C.) for 3 h after which time the yellow color had dissipated and the starting ketone was not detected by ¹H NMR. The solution was cooled to ambient temperature and then concentrated to provide a heterogeneous solution. The product was triturated with heptane (100 ml) and filtered to provide 29.24 g (92%) of the desired chlorobenzoxazinone as a white solid. m.p. 140.8° C.; ¹H NMR (300 MHz) δ 9.26 (b, 1H), 7.57 (s, 1H), 7.45 (dd, J=1.9, 8.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H); ¹³C NMR (75 MHz) δ 146.32, 132.88, 132.42, 130.27, 125.80, 122.83, 119.06, 116.79, 115.85, 0.013; ¹⁹F NMR (282 MHz) δ −79.5; IR (cm⁻¹) 3191, 1764, 1601, 1498, 1403, 1335, 1316, 1252, 1199, 1073, 991, 901, 874, 826, 683.

Example 22 Preparation of (±)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a 50 ml 3 neck flask equipped with a magnetic stir bar, a thermocouple probe and nitrogen inlet was charged 10 ml anhydrous THF and 2.2 eq cyclopropylacetylene (0.23 g, 3.4 mmol.). The solution was cooled to −50° C. and 2.0 eq. of n-hexyllithium in hexanes (1.8 M, 1.8 ml, 3.26 mmol.) was added dropwise via syringe. The internal temperature was maintained below −30° C. during the organolithium charge. The solution was aged for 30 minutes and then a solution of 0.44 g (1.55 mmol.) of the chlorobenzoxazinone in 5 ml THF was added dropwise. The reaction solution was maintained below −20° C. during the addition. The mixture was aged at −20° C. for 4 h after which time all of the starting material had been consumed by TLC. The mixture was then quenched while cold with saturated ammonium chloride solution and the layers separated. The organic solution was dried over sodium sulfate, concentrated to provide a light yellow solid. The product was then triturated with heptanes to provide 0.47 g (95%) of racemic title product as a white solid. HPLC: 99.8 area %; m.p. 183-6° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 7.54 (dd, J=2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, −1.32; ¹⁹F NMR (282 MHz, DMSO-d₆) δ −81.1; IR (cm⁻¹) 3316, 3094, 2250, 1752, 1602, 1498, 1196, 1186. HRMS calcd. for C₁₄H₁₀F₃ClNO₂ (M+H) 316.0352, found 316.0338. Anal. Calcd. for C₁₄H₉F₃ClNO₂: C, 53.27; H, 2.87; N, 4.45; Cl 11.23; F. 18.05. Found: C, 53.15; H, 2.73; N, 4.37; Cl, 11.10; F, 17.84.

Example 23 Preparation of (S)-6-Chloro-4-(1-pyridylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a 50 ml 3 neck flask equipped with a magnetic stir bar, thermocouple and nitrogen inlet was charged 20 ml anhydrous THF and 2.2 eq pyridylethyne (1.1 g, 10.2 mmol.). The solution was cooled to −50° C. and 2.0 eq. of n-hexyllithium in hexanes (1.8 M, 4.0 ml, 10.0 mmol.) was added dropwise via syringe. The internal temperature was maintained below −30° C. during the organolithium charge. The solution was aged for 30 minutes and then a solution of 1.5 g (5.2 mmol.) of the chlorobenzoxazinone from Example 21 in 15 ml THF was added dropwise. The reaction solution was maintained above −20° C. during the addition. The mixture was aged at −20° C. for 2 h at which time all of the starting material had been consumed by TLC. The mixture was then quenched while cold with saturated ammonium chloride solution and the layers separated. The organic solution was dried over sodium sulfate, concentrated to provide a brown solid. The product was purified by flash chromatography (hexanes/ethyl acetate; 3:1) and then triturated with heptanes to provide 1.06 g (57%) of the title compound as a white solid HPLC 99.8 area %; m.p. 185.8° C.; ¹H NMR (300 MHz) δ 9.62 (s, 1H), 8.68 (d, J=4.2 Hz, 1 H), 7.76 (dd, J=7.6, 9.5 Hz, 1H), 7.61 (d, J=5.7 Hz, 2H), 7.40 (m, 2 H), 6.91 (d, J=8.7 Hz, 1H; ¹³C NMR (75 MHz) δ 150.38, 148.20, 140.32, 136.57, 133.43, 132.06, 129.34, 128.30, 127.60, 124.65, 123.94, 120.13, 116.37, 114.01, 88.72, 78,75; ¹⁹F NMR (282 MHz) δ −81.4; IR (cm⁻¹)3245, 3157, 3069, 2946, 2876, 2252, 1757, 1603, 1581, 1498, 1467, 1428, 1401, 1305, 1256, 1243, 1186, 1142, 1401, 1304, 1256+, 1243, 1186, 1142, 1103, 1072, 1037, 997, 971, 940, 866, 822, 780, 740. MS FIA/PCI (M+H) 353 m/z.

Example 24

Preparation of (+/−)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 1-(t-Butyldimethylsilyl)-2-cyclopropylacetylene

To a stirred, cooled (0° C.) solution of 188 mL (658 mmol) of a 3.5 M solution of cyclopropylacetylene in toluene was added 200 mL of THF. The solution was re-cooled to 0° C. and treated with 264 mL (660 mmol) of a 2.5 M solution of n-BuLi in hexanes over 15 min. The solution was stirred an additional 10 min. at 0° C. and treated with 100 g(663 mmol) of t-butyldimethylsilyl chloride in 60 mL of THF over 10 min. After stirring 90 min. at 0° C. the reaction was quenched with saturated aq. NH₄Cl and poured into 500 mL of water. The mixture was extracted with 500 mL of ether, and the organic extract was washed three times with water and once with brine. Concentration under reduced pressure followed by distillation afforded 49 g(42%) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene as a colorless oil (b.p. 39-42° C. at 0.5 torr). ¹H NMR (CDCl₃, 300 MHz) δ 1.17-1.24(m, 1H); 0.95(s, 9H); 0.61-0.75(m, 4H); 0.00(s, 6H).

Part B: Preparation of 1-Deutero-1-ethynylcyclopropane

To a stirred, cooled(−30° C.) solution of 130 g(720 mmol) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene in 400 mL of THF was added 403 mL(1.01 mol) of a 2.5 M solution of n-BuLi in hexanes over 15 min. The solution was stirred 1.5 h at −20° C. and then treated with 49 mL(1.2 mol) of CD₃OD over 10 min. After stirring 10 min. at −10° C. the reaction was quenched with 10 mL of D₂O, followed 15 min later with 1 L of 20% aq. citric acid. The mixture was extracted with 1 L of ether, and the organic extract was washed sequentially with water, sat'd aq. NaHCO₃, and brine. The solution was dried(MgSO₄), concentrated under reduced pressure, and redissolved in 300 mL of THF. This solution was treated with 780 mL(350 mmol) of a 1 M solution of (n-Bu)₄NF in THF and stirred 6 h at ambient temperature. The solution was cooled to 0° C., washed with 1 L of water, and the aqueous phase was extracted with 150 mL of p-xylene. The organic extract was washed with 500 mL of water, and the combined aqueous phases were extracted with 70 mL of p-xylene. The two organic phases were combined, and washed 5 times with water and once with brine, dried(MgSO₄), and distilled. The fraction which boiled up to 105° C. at ambient pressure was collected to give 88 g of a solution having a deuterocyclopropylacetylene concentration of c. 43%. The remainder is primarily THF with some xylene and some 1-butene.

Part C: Preparation of (+/−) 6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled(−60° C.) solution of 12.6 g of a 60% solution of 1-deutero-1-ethynylcyclpropane in 65 mL of anhydrous THF was added 41 mL(102 mmol) of a 2.5M solution of n-BuLi in hexanes over 20 min. The solution was stirred 30 min. and charged with 9.7 g(33.9 mmol) of 4,6-dichloro-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one in 10 mL of THF over 2 min. The solution was warmed to −30° C. over 1 h, whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO₃ then brine. The solution was concentrated under reduced pressure, and the crude product was chromatographed on silica gel(elution with 2:1 hexanes-ether) to afford 5.8 g(54%) of (+/−) 6-chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 180-181° C. ¹H NMR(300 MHz, CDCl₃) δ 9.32(br. s, 1H); 7.50(m, 1H); 7.37(dd, 1H, J=8, 1 Hz); 6.95(d, 1H, J=8 Hz); 0.82-0.96(m, 4H). Chiral chromatographic resolution provides (−) 6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 133-134° C.

Example 25 Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of 2-Amino-6-fluoro-α-trifluoromethylbenzyl alcohol

To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2 mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes) provided 88 mg of title compound (108 mg theoretical, 82% yield).

Part B: Preparation of 3-Fluoro-2-trifluoroacetyltriphenylmethylaniline

To a solution of 2-amino-6-fluoro-α-trifluoromethyl-benzyl alcohol (88 mg, 0.2 mmol) in methylene chloride (6 mL) at room temperature was added manganese(IV)oxide (900 mg, 10xwt) and the resulting reaction mixture was allowed to stir at room temperature for 5 h. The reaction mixture is filtered through Celite and concentrated in vacuo. Chromatography (SiO₂, 5% EtOAc-hexanes) provided 52 mg of the title compound (90 mg theoretical, 58% yield).

Part C: Preparation of 2-Triphenylmethylamino-6-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol.

To a solution of 3-methyl-1-butyne (0.15 mL, 1.51 mmol) in THF (2 mL) at 0° C. was added 1.6 M nBuLi in hexane (0.84 mL, 1.34 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 6-fluoro-2-trifluoroacetylaniline (300 mg, 0.67 mmol) in THF (2 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part D: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude trityl protected amino-alcohol (crude product, 0.67 mmol) in methanol (5 mL) at room temperature was added concentrated HCl (0.1 mL) and the resulting reaction mixture is allowed to stir at room temperature for 0.25 h. The reaction mixture is concentrated in vacuo and the residue is taken up in ether (10 mL) and washed with saturated NaHCO₃. The ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography (SiO₂, 15% EtOAc-hexanes) provided 103 mg of the deprotected amino-alcohol (184 mg theoretical, 56% yield).

To a solution of amino-alcohol (103 mg, 0.37 mmol) in toluene (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) followed by a solution of 1.93M phosgene in toluene (0.25 mL, 0.48 mmol) and the resulting solution was allowed to stir at 0° C. for 1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 89 mg of the title compound (111 mg theoretical, 80% yield).

TABLE 1

Ex. # G R¹ R² m.p. (° C.) Mass Spec 1 6-Cl, 8-OH CF₃ C≡C—cycPr 332.0301 2(−) 6-Cl, 8-OH CF₃ C≡C—cycPr 170-172 3(−) 6-Cl, 8-OH CF₃ C≡C—cycPr 4 6-Cl, 8-F CF₃ C≡C—cycPr 169-171 334.0244 5 6-CH₃ iPr C≡C—cycPr   138-138.5 270.1494 6 6-CH₃ CF₃ C≡C—iPr 198-199 298.1047 7 6-COCH₃ CF₃ C≡C—cycPr 197-200 8 5,6-diF CF₃ 3-methyl-1- buten-1-yl 9 5,6-diF CF₃ C≡C—iPr 319.0616 12 6-Cl, 7-aza CF₃ C≡C—cycPr 317.0322 13 6-Cl CF₃ methoxyethoxy 14 6-Cl CF₃ n-propylamino 15 6-Cl CF₃ furan-2-yl-≡- 16 6-OMe CF₃ C≡C—Et 161-162 300.0841 17 6-Cl CF₃ ≡-(1′-OH—cycPr) 332.0296 18 5-F CF₃ ≡—iPr 22 6-Cl CF₃ ≡—cycPr 316.0352 23 6-Cl CF₃ ≡-2-pyridyl 353 (M + H) 24 6-Cl CF₃ ≡-(1-deutero- 133-134 cycloprop-1-yl) 25 5-F CF₃ ≡—iPr 26 6-Cl, 8-OMe CF₃ C≡C—cycPr 346.0477 27 6-Cl, 7-OH CF₃ C≡C—cycPr 332.0286 28 6-Cl, 8-F CF₃ C≡C—Et 191-192 339.0525 (M + NH₄ ⁺) 29 6-Cl, 8-F CF₃ CH₂CH₂CH(CH₃)₂ 160-162 340 (MH⁺) 30 5,6-diF CF₃ C≡C—cycPr 318.0550 (MH⁺) 31 5,6-diF CF₃ C≡C—iPr amorphous 32 5,6-diF CF₃ C≡C—nPr 320.0691 33 5,6-diF CF₃ C≡C—Et 306.0550 (MH⁺) 34 5,6-diF CF₃ C≡C—Me 217 35 5,6-diF CF₃ CH₂CH₂CH₂CH₂CH₃ 324.1008 36 5,6-diF CF₃ CH₂CH₂CH(CH₃)₂ 324.1003 37 5,6-diF CF₃ CH₂CH₂CH₂CH₃ 310.0878 38 5,6-OCH₂O— CF₃ C≡C—cycPr 223-225 326.0639 39 5,6-OCH₂O— CF₃ C≡C—iPr 240 328.0797 40 5,6-OCH₂O— CF₃ C≡C—nPr 208-210 41 5,6-OCH₂O— CF₃ C≡C—Et 230-232 42 5,6-OCH₂O— CF₃ CH₂C≡C—CH₂CH₃ 215-217 328.0800 43 5,6-OCH₂O— CF₃ CH₂C≡C—CH₃ 207-208 314.0640 44 5,6-OCH₂O— CF₃ CH₂CH₂CH(CH₃)₂ 199-200 45 6-OMe CF₃ C≡C—cycPr 155-157 312.0835 46 6-OMe CF₃ C≡C—cycPr 143-144 312.0843 47 6-OMe CF₃ C≡C—cycPr 142-144 312.0836 48 6-OMe CF₃ C≡C—iPr 158-159 314.0998 49 6-OMe CF₃ C≡C—nPr 148-150 314.1007 50 6-OMe CF₃ C≡C—Me 177-180 286.0691 51 6-OMe CF₃ CH₂C≡C—CH₂CH₃ 119-122 314.0989 52 6-OMe CF₃ CH₂CH₂CH(CH₃)₂ 318 (MH⁺) 53 6-OMe CF₃ CH₂CH₂CH₂CH₃ 304.1167 54 6-OMe CF₃ CH₂CH₂—Ph 352.1153 55 6-OMe, 8-F CF₃ C≡C—cycPr 188-189 330.0738 56 6-NMe₂ CF₃ C≡C—cycPr 325.1173 57 6-NMe₂ CF₃ C≡C—iPr 327.1322 58 6-NMe₂ CF₃ CH₂CH₂CH₂CH₂CH₃ 331.1641 59 6-NMe₂ CF₃ CH₂CH₂CH(CH₃)₂ 331.1637 60 6-COCH₃ CF₃ C≡C—Et 180-183 61 6-CH₃ CF₃ C≡C—cycPr 189 296.0905 62 6-CH₃ CF₃ C≡C—Et 222 284.0882 63 6,8-diCl CF₃ C≡C—cycPr 152-153 348.9870 64 6,8-diCl CF₃ CH₂CH₂—Ph 389.0188 (M⁺) 65 5,6,8-triF CF₃ C≡C—cycPr amorphous 66 5,6,8-triF CF₃ C≡C—iPr amorphous 67 5,6,8-triF CF₃ C≡C—nPr amorphous 68 5,6,8-triF CF₃ C≡C—Et amorphous 69 5,8-diF CF₃ C≡C—cycPr 335.0834 (M + NH₄ ⁺) 70 5,8-diF CF₃ C≡C—iPr 320.0710 (MH⁺) 71 5,8-diF CF₃ C≡C—nPr 337.0970 (M + NH₄ ⁺) 72 5,8-diF CF₃ C≡C—Et 323.8817 (M + NH₄ ⁺) 73 6-iPr CF₃ C≡C—cycPr 324.1203 74 6-iPr CF₃ C≡C—iPr 326.1361 75 6-iPr CF₃ C≡C—Ph 360.1204 76 6-iPr CF₃ CH₂CH₂CH₂CH₂CH₃ 330.1672 77 6-iPr CF₃ CH₂CH₂—iPr 330.1673 78 6-iPr CF₃ CH₂CH₂—Ph 364.1517 79 6-OCF₃ CF₃ C≡C—cycPr 366.0561 80 6-OCF₃ CF₃ C≡C—iPr 368.0712 81 6-OCF₃ CF₃ C≡C—Ph 401.0475 82 6-OCF₃ CF₃ CH₂CH₂CH₂CH₂CH₃ 372.1018 83 6-OCF₃ CF₃ CH₂CH₂—iPr 372.1039 84 6-OCF₃ CF₃ CH₂CH₂—Ph 405.0795 85 H CF₃ CH₂CH₂—Ph 282.0735 86 H CF₃ C≡C—iPr 284.0894 87 H CF₃ C≡C—Ph 318.0748 88 H CF₃ CH₂CH₂CH₂CH₂CH₃ 288.1201 89 H CF₃ CH₂CH₂—iPr 121-122 90 H CF₃ CH₂CH₂—Ph 322.1055 91 6-Ph CF₃ C≡C—cycPr 185-186 358.1055 92 6-Ph CF₃ C≡C—iPr 179-180 360.1211 93 6-Ph CF₃ C≡C—nPr 143-144 360.1211 94 6-Ph CF₃ C≡C—iBu 163-164 374.1352 95 6-Ph CF₃ C≡C—Et 195 346.1055 96 6-Ph CF₃ CH₂CH₂—iPr 147-148 364.1524 97 6-OMe iPr C≡C—cycPr 286.1428 98 6-OMe iPr C≡C—iPr 288.1583 99 6-CH₃ cycPr C≡C—iPr 133-134 270.1498 100 6-CH₃ iPr C≡C—iPr 133-134 272.1648 101 6-CH₃ Et C≡C—iPr 138-139 258.1505 102 6-CH₃ Et C≡C—Et 138.5-139   244.1333 103 6,7-diCl cycPr C≡C—iPr 104 6,7-diCl iPr C≡C—iPr amorphous 105 7-Cl cycPr C≡C—cycPr 288.0783 106 7-Cl cycPr C≡C—iPr 290.0941 107 7-Cl cycPr C≡C—iBu 117-118 304.1110 108 7-Cl iPr C≡C—cycPr 290.0940 109 7-Cl iPr C≡C—iPr 292.1103 110 6-Cl, 8-aza CF₃ C≡C—cycPr 317.0317 111 6-Cl, 8-aza CF₃ C≡C—iPr 319 (MH⁺) 112 6-Cl, 8-aza CF₃ CH₂CH₂—Ph 214-215 357.0625 113 6-OCH₃, 7-aza CF₃ C≡C—cycPr 181-182 313.0800 114 6-aza CF₃ C≡C—cycPr *Unless otherwise noted, stereochemistry is (+/−).

TABLE 2

Ex. # G R¹ R² 201 6-Cl, 8-F CF₃ C≡C-iPr 202 6-Cl, 8-F CF₃ C≡C-nPr 203 6-Cl, 8-F CF₃ C≡C-Bu 204 6-Cl, 8-F CF₃ C≡C-iBu 205 6-Cl, 8-F CF₃ C≡C-tBu 206 6-Cl, 8-F CF₃ C≡C-Me 207 6-Cl, 8-F CF₃ C≡C-Ph 208 6-Cl, 8-F CF₃ C≡C-(2-Cl)Ph 209 6-Cl, 8-F CF₃ C≡C-(3-Cl)Ph 210 6-Cl, 8-F CF₃ C≡C-(2-F)Ph 211 6-Cl, 8-F CF₃ C≡C-(3-F)Ph 212 6-Cl, 8-F CF₃ C≡C-(2-OH)Ph 213 6-Cl, 8-F CF₃ C≡C-(3-OH)Ph 214 6-Cl, 8-F CF₃ C≡C-(2-OMe)Ph 215 6-Cl, 8-F CF₃ C≡C-(3-OMe)Ph 216 6-Cl, 8-F CF₃ C≡C-(2-CN)Ph 217 6-Cl, 8-F CF₃ C≡C-(3-CN)Ph 218 6-Cl, 8-F CF₃ C≡C-(2-NH₂)Ph 219 6-Cl, 8-F CF₃ C≡C-(3-NH₂)Ph 220 6-Cl, 8-F CF₃ C≡C-(2-NMe₂)Ph 221 6-Cl, 8-F CF₃ C≡C-(3-NMe₂)Ph 222 6-Cl, 8-F CF₃ C≡C-2-Pyridyl 223 6-Cl, 8-F CF₃ C≡C-3-Pyridyl 224 6-Cl, 8-F CF₃ C≡C-4-Pyridyl 225 6-Cl, 8-F CF₃ C≡C-2-furanyl 226 6-Cl, 8-F CF₃ C≡C-3-furanyl 227 6-Cl, 8-F CF₃ C≡C-2-thienyl 228 6-Cl, 8-F CF₃ C≡C-3-thienyl 229 6-Cl, 8-F CF₃ CH═CH-cycPr 230 6-Cl, 8-F CF₃ CH═CH-iPr 231 6-Cl, 8-F CF₃ CH═CH-nPr 232 6-Cl, 8-F CF₃ CH═CH-Bu 233 6-Cl, 8-F CF₃ CH═CH-iBu 234 6-Cl, 8-F CF₃ CH═CH-tBu 235 6-Cl, 8-F CF₃ CH═CH-Et 236 6-Cl, 8-F CF₃ CH═CH-Me 237 6-Cl, 8-F CF₃ CH═CH-Ph 238 6-Cl, 8-F CF₃ CH═CH-2-Pyridyl 239 6-Cl, 8-F CF₃ CH═CH-3-Pyridyl 240 6-Cl, 8-F CF₃ CH═CH-4-Pyridyl 241 6-Cl, 8-F CF₃ CH═CH-2-furanyl 242 6-Cl, 8-F CF₃ CH═CH-3-furanyl 243 6-Cl, 8-F CF₃ CH═CH-2-thienyl 244 6-Cl, 8-F CF₃ CH═CH-3-thienyl 245 6-Cl, 8-F CF₃ CH₂CH₂CH₂CH₂CH₃ 246 6-Cl, 8-F CF₃ CH₂CH₂CH₂CH₃ 247 6-Cl, 8-F CF₃ CH₂CH₂-cycPr 248 6-Cl, 8-F CF₃ CH₂CH₂-tBu 249 6-Cl, 8-F CF₃ CH₂CH₂-Ph 250 6-Cl, 8-F CF₃ CH₂CH₂-2-Pyridyl 251 6-Cl, 8-F CF₃ CH₂CH₂-3-Pyridyl 252 6-Cl, 8-F CF₃ CH₂CH₂-4-Pyridyl 253 6-Cl, 8-F CF₃ CH₂CH₂-2-furanyl 254 6-Cl, 8-F CF₃ CH₂CH₂-3-furanyl 255 6-Cl, 8-F CF₃ CH₂CH₂-2-thienyl 256 6-Cl, 8-F CF₃ CH₂CH₂-3-thienyl 257 5,6-diF CF₃ C≡C-Bu 258 5,6-diF CF₃ C≡C-iBu 259 5,6-diF CF₃ C≡C-tBu 260 5,6-diF CF₃ C≡CCH₂CH₂OH 261 5,6-diF CF₃ C≡C-CH(OH)Me 262 5,6-diF CF₃ C≡C-Ph 263 5,6-diF CF₃ C≡C-(2-Cl)Ph 264 5,6-diF CF₃ C≡C-(3-Cl)Ph 265 5,6-diF CF₃ C≡C-(4-Cl)Ph 266 5,6-diF CF₃ C≡C-(2-F)Ph 267 5,6-diF CF₃ C≡C-(3-F)Ph 268 5,6-diF CF₃ C≡C-(4-F)Ph 269 5,6-diF CF₃ C≡C-(2-OH)Ph 270 5,6-diF CF₃ C≡C-(3-OH)Ph 271 5,6-diF CF₃ C≡C-(4-OH)Ph 272 5,6-diF CF₃ C≡C-(2-OMe)Ph 273 5,6-diF CF₃ C≡C-(3-OMe)Ph 274 5,6-diF CF₃ C≡C-(4-OMe)Ph 275 5,6-diF CF₃ C≡C-(2-CN)Ph 276 5,6-diF CF₃ C≡C-(3-CN)Ph 277 5,6-diF CF₃ C≡C-(4-CN)Ph 278 5,6-diF CF₃ C≡C-(2-NO₂)Ph 279 5,6-diF CF₃ C≡C-(3-NO₂)Ph 280 5,6-diF CF₃ C≡C-(4-NO₂)Ph 281 5,6-diF CF₃ C≡C-(2-NH₂)Ph 282 5,6-diF CF₃ C≡C-(3-NH₂)Ph 283 5,6-diF CF₃ C≡C-(4-NH₂)Ph 284 5,6-diF CF₃ C≡C-(2-NMe₂)Ph 285 5,6-diF CF₃ C≡C-(3-NMe₂)Ph 286 5,6-diF CF₃ C≡C-(4-NMe₂)Ph 287 5,6-diF CF₃ C≡C-2-Pyridyl 288 5,6-diF CF₃ C≡C-3-Pyridyl 289 5,6-diF CF₃ C≡C-4-Pyridyl 290 5,6-diF CF₃ C≡C-2-furanyl 291 5,6-diF CF₃ C≡C-3-furanyl 292 5,6-diF CF₃ C≡C-2-thienyl 293 5,6-diF CF₃ C≡C-3-thienyl 294 5,6-diF CF₃ C≡C-2-oxazolyl 295 5,6-diF CF₃ C≡C-2-thiazolyl 296 5,6-diF CF₃ C≡C-4-isoxazolyl 297 5,6-diF CF₃ C≡C-2-imidazolyl 298 5,6-diF CF₃ CH₂C≡C-CH₃ 299 5,6-diF CF₃ CH₂C≡C-CH₂CH₃ 300 5,6-diF CF₃ CH═CH-cycPr 301 5,6-diF CF₃ CH═CH-iPr 302 5,6-diF CF₃ CH═CH-nPr 303 5,6-diF CF₃ CH═CH-Bu 304 5,6-diF CF₃ CH═CH-iBu 305 5,6-diF CF₃ CH═CH-tBu 306 5,6-diF CF₃ CH═CH-Et 307 5,6-diF CF₃ CH═CH-Me 308 5,6-diF CF₃ CH═CH-Ph 309 5,6-diF CF₃ CH═CH-2-Pyridyl 310 5,6-diF CF₃ CH═CH-3-Pyridyl 311 5,6-diF CF₃ CH═CH-4-Pyridyl 312 5,6-diF CF₃ CH═CH-2-furanyl 313 5,6-diF CF₃ CH═CH-3-furanyl 314 5,6-diF CF₃ CH═CH-2-thienyl 315 5,6-diF CF₃ CH═CH-3-thienyl 316 5,6-diF CF₃ CH₂CH₂CH₃ 317 5,6-diF CF₃ CH₂CH₂-cycPr 318 5,6-diF CF₃ CH₂CH₂-tBu 319 5,6-diF CF₃ CH₂CH₂CH₂CH₂OH 320 5,6-diF CF₃ CH₂CH₂-CH(OH)Me 321 5,6-diF CF₃ CH₂CH₂Ph 322 5,6-diF CF₃ CH₂CH₂-(2-Cl)Ph 323 5,6-diF CF₃ CH₂CH₂-(3-Cl)Ph 324 5,6-diF CF₃ CH₂CH₂-(4-Cl)Ph 325 5,6-diF CF₃ CH₂CH₂-(2-F)Ph 326 5,6-diF CF₃ CH₂CH₂-(3-F)Ph 327 5,6-diF CF₃ CH₂CH₂-(4-F)Ph 328 5,6-diF CF₃ CH₂CH₂-(2-OH)Ph 329 5,6-diF CF₃ CH₂CH₂-(3-OH)Ph 330 5,6-diF CF₃ CH₂CH₂-(4-OH)Ph 331 5,6-diF CF₃ CH₂CH₂-(2-OMe)Ph 332 5,6-diF CF₃ CH₂CH₂-(3-OMe)Ph 333 5,6-diF CF₃ CH₂CH₂-(4-OMe)Ph 334 5,6-diF CF₃ CH₂CH₂-(2-CN)Ph 335 5,6-diF CF₃ CH₂CH₂-(3-CN)Ph 336 5,6-diF CF₃ CH₂CH₂-(4-CN)Ph 337 5,6-diF CF₃ CH₂CH₂-(2-NO₂)Ph 338 5,6-diF CF₃ CH₂CH₂-(3-NO₂)Ph 339 5,6-diF CF₃ CH₂CH₂-(4-NO₂)Ph 340 5,6-diF CF₃ CH₂CH₂-(2-NH₂)Ph 341 5,6-diF CF₃ CH₂CH₂-(3-NH₂)Ph 342 5,6-diF CF₃ CH₂CH₂-(4-NH₂)Ph 343 5,6-diF CF₃ CH₂CH₂-(2- NMe₂) Ph 344 5,6-diF CF₃ CH₂CH₂-(3- NMe₂)Ph 345 5,6-diF CF₃ CH₂CH₂-(4- NMe₂)Ph 346 5,6-diF CF₃ CH₂CH₂-2-Pyridyl 347 5,6-diF CF₃ CH₂CH₂-3-Pyridyl 348 5,6-diF CF₃ CH₂CH₂-4-Pyridyl 349 5,6-diF CF₃ CH₂CH₂-2-furanyl 350 5,6-diF CF₃ CH₂CH₂-3-furanyl 351 5,6-diF CF₃ CH₂CH₂-2-thienyl 352 5,6-diF CF₃ CH₂CH₂-3-thienyl 353 5,6-diF CF₃ CH₂CH₂-2- oxazolyl 354 5,6-diF CF₃ CH₂CH₂-2- thiazolyl 355 5,6-diF CF₃ CH₂CH₂-4- isoxazolyl 356 5,6-diF CF₃ CH₂CH₂-2- imidazolyl 357 5,6-diCl CF₃ C≡C-cycPr 358 5,6-diCl CF₃ C≡C-iPr 359 5,6-diCl CF₃ C≡C-nPr 360 5,6-diCl CF₃ C≡C-Bu 361 5,6-diCl CF₃ C≡C-iBu 362 5,6-diCl CF₃ C≡C-tBu 363 5,6-diCl CF₃ C≡C-Et 364 5,6-diCl CF₃ C≡C-Me 365 5,6-diCl CF₃ C≡CCH₂CH₂OH 366 5,6-diCl CF₃ C≡C-CH(OH)Me 367 5,6-diCl CF₃ C≡C-Ph 368 5,6-diCl CF₃ C≡C-(2-Cl)Ph 369 5,6-diCl CF₃ C≡C-(3-Cl)Ph 370 5,6-diCl CF₃ C≡C-(4-Cl)Ph 371 5,6-diCl CF₃ C≡C-(2-F)Ph 372 5,6-diCl CF₃ C≡C-(3-F)Ph 373 5,6-diCl CF₃ C≡C-(4-F)Ph 374 5,6-diCl CF₃ C≡C-(2-OH)Ph 375 5,6-diCl CF₃ C≡C-(3-OH)Ph 376 5,6-diCl CF₃ C≡C-(4.OH)Ph 377 5,6-diCl CF₃ C≡C-(2-OMe)Ph 378 5,6-diCl CF₃ C≡C-(3-OMe)Ph 379 5,6-diCl CF₃ C≡C-(4-OMe)Ph 380 5,6-diCl CF₃ C≡C-(2-CN)Ph 381 5,6-diCl CF₃ C≡C-(3-CN)Ph 382 5,6-diCl CF₃ C≡C-(4-CN)Ph 383 5,6-diCl CF₃ C≡C-(2-NO₂)Ph 384 5,6-diCl CF₃ C≡C-(3-NO₂)Ph 385 5,6-diCl CF₃ C≡C-(4-NO₂)Ph 386 5,6-diCl CF₃ C≡C-(2-NH₂)Ph 387 5,6-diCl CF₃ C≡C-(3-NH₂)Ph 388 5,6-diCl CF₃ C≡C-(4-NH₂)Ph 389 5,6-diCl CF₃ C≡C-(2-NMe₂)Ph 390 5,6-diCl CF₃ C≡C-(3-NMe₂)Ph 391 5,6-diCl CF₃ C≡C-(4-NMe₂)Ph 392 5,6-diCl CF₃ C≡C-2-Pyridyl 393 5,6-diCl CF₃ C≡C-3-Pyridyl 394 5,6-diCl CF₃ C≡C-4-Pyridyl 395 5,6-diCl CF₃ C≡C-2-furanyl 396 5,6-diCl CF₃ C≡C-3-furanyl 397 5,6-diCl CF₃ C≡C-2-thienyl 398 5,6-diCl CF₃ C≡C-3-thienyl 399 5,6-diCl CF₃ CH═CH-cycPr 400 5,6-diCl CF₃ CH═CH-iPr 401 5,6-diCl CF₃ CH═CH-nPr 402 5,6-diCl CF₃ CH═CH-Bu 403 5,6-diCl CF₃ CH═CH-iBu 404 5,6-diCl CF₃ CH═CH-tBu 405 5,6-diCl CF₃ CH═CH-Et 406 5,6-diCl CF₃ CH═CH-Me 407 5,6-diCl CF₃ CH═CH-Ph 408 5,6-diCl CF₃ CH═CH-2-Pyridyl 409 5,6-diCl CF₃ CH═CH-3-Pyridyl 410 5,6-diCl CF₃ CH═CH-4-Pyridyl 411 5,6-diCl CF₃ CH═CH-2-furanyl 412 5,6-diCl CF₃ CH═CH-3-furanyl 413 5,6-diCl CF₃ CH═CH-2-thienyl 414 5,6-diCl CF₃ CH═CH-3-thienyl 415 5,6-diCl CF₃ CH₂CH₂CH₂CH₂CH₃ 416 5,6-diCl CF₃ CH₂CH₂CH(CH₃)₂ 417 5,6-diCl CF₃ CH₂CH₂CH₂CH₃ 418 5,6-diCl CF₃ CH₂CH₂-cycPr 419 5,6-diCl CF₃ CH₂CH₂-tBu 420 5,6-diCl CF₃ CH₂CH₂CH₂CH₂OH 421 5,6-diCl CF₃ CH₂CH₂-CH(OH)Me 422 5,6-diCl CF₃ CH₂CH₂-Ph 423 5,6-diCl CF₃ CH₂CH₂-2-Pyridyl 424 5,6-diCl CF₃ CH₂CH₂-3-Pyridyl 425 5,6-diCl CF₃ CH₂CH₂-4-Pyridyl 426 5,6.-diCl CF₃ CH₂CH₂-2-furanyl 427 5,6-diCl CF₃ CH₂CH₂-3-furanyl 428 5,6-diCl CF₃ CH₂CH₂-2-thienyl 429 5,6-diCl CF₃ CH₂CH₂-3-thienyl 430 5-Cl,6-F CF₃ C≡C-cycPr 431 5-Cl,6-F CF₃ C≡C-iPr 432 5-Cl,6-F CF₃ C≡C-nPr 433 5-Cl,6-F CF₃ C≡C-Bu 434 5-Cl,6-F CF₃ C≡C-iBu 435 5-Cl,6-F CF₃ C≡C-tBu 436 5-Cl,6-F CF₃ C≡C-Et 437 5-Cl,6-F CF₃ C≡C-Me 438 5-Cl,6-F CF₃ C≡CCH₂CH₂OH 439 5-Cl,6-F CF₃ C≡C-CH(OH)Me 440 5-Cl,6-F CF₃ C≡C-Ph 441 5-Cl,6-F CF₃ C≡C-(2-Cl)Ph 442 5-Cl,6-F CF₃ C≡C-(3-Cl)Ph 443 5-Cl,6-F CF₃ C≡C-(4-Cl)Ph 444 5-Cl,6-F CF₃ C≡C-(2-F)Ph 445 5-Cl,6-F CF₃ C≡C-(3-F)Ph 446 5-Cl,6-F CF₃ C≡C-(4-F)Ph 447 5-Cl,6-F CF₃ C≡C-(2-OH)Ph 448 5-Cl,6-F CF₃ C≡C-(3-OH)Ph 449 5-Cl,6-F CF₃ C≡C-(4-OH)Ph 450 5-Cl,6-F CF₃ C≡C-(2-OMe)Ph 451 5-Cl,6-F CF₃ C≡C-(3-OMe)Ph 452 5-Cl,6-F CF₃ C≡C-(4-OMe)Ph 453 5-Cl,6-F CF₃ C≡C-(2-CN)Ph 454 5-Cl,6-F CF₃ C≡C-(3-CN)Ph 455 5-Cl,6-F CF₃ C≡C-(4-CN)Ph 456 5-Cl,6-F CF₃ C≡C-(2-NO₂)Ph 457 5-Cl,6-F CF₃ C≡C-(3-NO₂)Ph 458 5-Cl,6-F CF₃ C≡C-(4-NO₂)Ph 459 5-Cl,6-F CF₃ C≡C-(2-NH₂)Ph 460 5-Cl,6-F CF₃ C≡C-(3-NH₂)Ph 461 5-Cl,6-F CF₃ C≡C-(4-NH₂)Ph 462 5-Cl,6-F CF₃ C≡C-(2-NMe₂)Ph 463 5-Cl,6-F CF₃ C≡C-(3-NMe₂)Ph 464 5-Cl,6-F CF₃ C≡C-(4-NMe₂)Ph 465 5-Cl,6-F CF₃ C≡C-2-Pyridyl 466 5-Cl,6-F CF₃ C≡C-3-Pyridyl 467 5-Cl,6-F CF₃ C≡C-4-Pyridyl 468 5-Cl,6-F CF₃ C≡C-2-furanyl 469 5-Cl,6-F CF₃ C≡C-3-furanyl 470 5-Cl,6-F CF₃ C≡C-2-thienyl 471 5-Cl,6-F CF₃ C≡C-3-thienyl 472 5-Cl,6-F CF₃ CH═CH-cycPr 473 5-Cl,6-F CF₃ CH═CH-iPr 474 5-Cl,6-F CF₃ CH═CH-nPr 475 5-Cl,6-F CF₃ CH═CH-Bu 476 5-Cl,6-F CF₃ CH═CH-iBu 477 5-Cl,6-F CF₃ CH═CH-tBu 478 5-Cl,6-F CF₃ CH═CH-Et 479 5-Cl,6-F CF₃ CH═CH-Me 480 5-Cl,6-F CF₃ CH═CH-Ph 481 5-Cl,6-F CF₃ CH═CH-2-Pyridyl 482 5-Cl,6-F CF₃ CH═CH-3-Pyridyl 483 5-Cl,6-F CF₃ CH═CH-4-Pyridyl 484 5-Cl,6-F CF₃ CH═CH-2-furanyl 485 5-Cl,6-F CF₃ CH═CH-3-furanyl 486 5-Cl,6-F CF₃ CH═CH-2-thienyl 487 5-Cl,6-F CF₃ CH═CH-3-thienyl 488 5-Cl,6-F CF₃ CH₂CH₂CH₂CH₂CH₃ 489 5-Cl,6-F CF₃ CH₂CH₂CH(CH₃)₂ 490 5-Cl,6-F CF₃ CH₂CH₂CH₂CH₃ 491 5-Cl,6-F CF₃ CH₂CH₂-cycPr 492 5-Cl,6-F CF₃ CH₂CH₂-tBu 493 5-Cl,6-F CF₃ CH₂CH₂CH₂CH₂OH 494 5-Cl,6-F CF₃ CH₂CH₂-CH(OH)Me 495 5-Cl,6-F CF₃ CH₂CH₂-Ph 496 5-Cl,6-F CF₃ CH₂CH₂-2-Pyridyl 497 5-Cl,6-F CF₃ CH₂CH₂-3-Pyridyl 498 5-Cl,6-F CF₃ CH₂CH₂-4-Pyridyl 499 5-Cl,6-F CF₃ CH₂CH₂-2-furanyl 500 5-Cl,6-F CF₃ CH₂CH₂-3-furanyl 501 5-Cl,6-F CF₃ CH₂CH₂-2-thienyl 502 5-Cl,6-F CF₃ CH₂CH₂-3-thienyl 503 5,6-OCH₂O— CF₃ C≡C-Bu 504 5,6-OCH₂O— CF₃ C≡C-iBu 505 5,6-OCH₂O— CF₃ C≡C-tBu 506 5,6-OCH₂O— CF₃ C≡C-Me 507 5,6-OCH₂O— CF₃ C≡CCH₂CH₂OH 508 5,6-OCH₂O— CF₃ C≡C-CH(OH)Me 509 5,6-OCH₂O— CF₃ C≡C-Ph 510 5,6-OCH₂O— CF₃ C≡C-(2-Cl)Ph 511 5,6-OCH₂O— CF_(3.) C≡C-(3-Cl)Ph 512 5,6-OCH₂O— CF₃ C≡C-(4-Cl)Ph 513 5,6-OCH₂O— CF₃ C≡C-(2-F)Ph 514 5,6-OCH₂O— CF₃ C≡C-(3-F)Ph 515 5,6-CCH₂O— CF₃ C≡C-(4-F)Ph 516 5,6-OCH₂O— CF₃ C≡C-(2-OH)Ph 517 5,6-OCH₂O— CF₃ C≡C-(3-OH)Ph 518 5,6-OCH₂O— CF₃ C≡C-(4-OH)Ph 519 5,6-OCH₂O— CF₃ C≡C-(2-OMe)Ph 520 5,6-OCH₂O— CF₃ C≡C-(3-OMe)Ph 521 5,6-OCH₂O— CF₃ C≡C-(4-OMe)Ph 522 5,6-OCH₂O— CF₃ C≡C-(2-CN)Ph 523 5,6-OCH₂O— CF₃ C≡C-(3-CN)Ph 524 5,6-OCH₂O— CF₃ C≡C-(4-CN)Ph 525 5,6-OCH₂O— CF₃ C≡C-(2-NO₂)Ph 526 5,6-OCH₂O— CF₃ C≡C-(3-NO₂)Ph 527 5,6-OCH₂O— CF₃ C≡C-(4-NO₂)Ph 528 5,6-OCH₂O— CF₃ C≡C-(2-NH₂)Ph 529 5,6-OCH₂O— CF₃ C≡C-(3-NH₂)Ph 530 5,6-OCH₂O— CF₃ C≡C-(4-NH₂)Ph 531 5,6-OCH₂O— CF₃ C≡C-(2-NMe₂)Ph 532 5,6-OCH₂O— CF₃ C≡C-(3-NMe₂)Ph 533 5,6-OCH₂O— CF₃ C≡C-(4-NMe₂)Ph 534 5,6-OCH₂O— CF₃ C≡C-2-Pyridyl 535 5,6-OCH₂O— CF₃ C≡C-3-Pyridyl 536 5,6-OCH₂O— CF₃ C≡C-4-Pyridyl 537 5,6-OCH₂O— CF₃ C≡C-2-furanyl 538 5,6-OCH₂O— CF₃ C≡C-3-furanyl 539 5,6-OCH₂O— CF₃ C≡C-2-thienyl 540 5,6-OCH₂O— CF₃ C≡C-3-thienyl 541 5,6-OCH₂O— CF₃ CH═CH-cycPr 542 5,6-OCH₂O— CF₃ CH═CH-iPr 543 5,6-OCH₂O— CF₃ CH═CH-nPr 544 5,6-OCH₂O— CF₃ CH═CH-Bu 545 5,6-OCH₂O— CF₃ CH═CH-iBu 546 5,6-CCH₂O— CF₃ CH═CH-tBu 547 5,6-OCH₂O— CF₃ CH═CH-Et 548 5,6-OCH₂O— CF₃ CH═CH-Me 549 5,6-OCH₂O— CF₃ CH═CH-Ph 550 5,6-OCH₂O— CF₃ CH═CH-2-Pyridyl 551 5,6-OCH₂O— CF₃ CH═CH-3-Pyridyl 552 5,6-OCH₂O— CF₃ CH═CH-4-Pyridyl 553 5,6-OCH₂O— CF₃ CH═CH-2-furanyl 554 5,6-OCH₂O— CF₃ CH═CH-3-furanyl 555 5,6-OCH₂O— CF₃ CH═CH-2-thienyl 556 5,6-OCH₂O— CF₃ CH═CH-3-thienyl 557 5,6-OCH₂O— CF₃ CH₂CH₂CH₂CH₂CH₃ 558 5,6-OCH₂O— CF₃ CH₂CH₂CH₂CH₃ 559 5,6-OCH₂O— CF₃ CH₂CH₂-cycPr 560 5,6-OCH₂O— CF₃ CH₂CH₂-tBu 561 5,6-OCH₂O— CF₃ CH₂CH₂CH₂CH₂CH 562 5,6-OCH₂O— CF₃ CH₂CH₂-CH(CH)Me 563 5,6-OCH₂O— CF₃ CH₂CH₂-Ph 564 5,6-OCH₂O— CF₃ CH₂CH₂-2-Pyridyl 565 5,6-OCH₂O— CF₃ CH₂CH₂-3-Pyridyl 566 5,6-OCH₂O— CF₃ CH₂CH₂-4-Pyridyl 567 5,6-OCH₂O— CF₃ CH₂CH₂-2-furanyl 568 5,6-OCH₂O— CF₃ CH₂CH₂-3-furanyl 569 5,6-OCH₂O— CF₃ CH₂CH₂-2-thienyl 570 5,6-OCH₂O— CF₃ CH₂CH₂-3-thienyl 571 5-F CF₃ C≡C-cycPr 572 5-F CF₃ C≡C-iPr 573 5-F CF₃ C≡C-nPr 574 5-F CF₃ C≡C-Bu 575 5-F CF₃ C≡C-iBu 576 5-F CF₃ C≡C-tBu 577 5-F CF₃ C≡C-Et 578 5-F CF₃ C≡C-Me 579 5-F CF₃ C≡OCH₂CH₂OH 580 5-F CF₃ C≡C-CH(OH)Me 581 5-F CF₃ C≡C-Ph 582 5-F CF₃ C≡C-(2-Cl)Ph 583 5-F CF₃ C≡C-(3-Cl)Ph 584 5-F CF₃ C≡C-(4-Cl)Ph 585 5-F CF₃ C≡C-(2-F)Ph 586 5-F CF₃ C≡C-(3-F)Ph 587 5-F CF₃ C≡C-(4-F)Ph 588 5-F CF₃ C≡C-(2-OH)Ph 589 5-F CF₃ C≡C-(3-OH)Ph 590 5-F CF₃ C≡C-(4-OH)Ph 591 5-F CF₃ C≡C-(2-OMe)Ph 592 5-F CF₃ C≡C-(3-OMe)Ph 593 5-F CF₃ C≡C-(4-OMe)Ph 594 5-F CF₃ C≡C-(2-CN)Ph 595 5-F CF₃ C≡C-(3-CN)Ph 596 5-F CF₃ C≡C-(4-CN)Ph 597 5-F CF₃ C≡C-(2-NO₂)Ph 598 5-F CF₃ C≡C-(3-NO₂)Ph 599 5-F CF₃ C≡C-(4-NO₂)Ph 600 5-F CF₃ C≡C-(2-NH₂)Ph 601 5-F CF₃ C≡C-(3-NH₂)Ph 602 5-F CF₃ C≡C-(4-NH₂)Ph 603 5-F CF₃ C≡C-(2-NMe₂)Ph 604 5-F CF₃ C≡C-(3-NMe₂)Ph 605 5-F CF₃ C≡C-(4-NMe₂)Ph 606 5-F CF₃ C≡C-2-Pyridyl 607 5-F CF₃ C≡C-3-Pyridyl 608 5-F CF₃ C≡C-4-Pyridyl 609 5-F CF₃ C≡C-2-furanyl 610 5-F CF₃ C≡C-3-furanyl 611 5-F CF₃ C≡C-2-thienyl 612 5-F CF₃ C≡C-3-thienyl 613 5-F CF₃ CH═CH-cycPr 614 5-F CF₃ CH═CH-iPr 615 5-F CF₃ CH═CH-nPr 616 5-F CF₃ CH═CH-Bu 617 5-F CF₃ CH═CH-iBu 618 5-F CF₃ CH═CH-tBu 619 5-F CF₃ CH═CH-Et 620 5-F CF₃ CH═CH-Me 621 5-F CF₃ CH═CH-Ph 622 5-F CF₃ CH═CH-2-Pyridyl 623 5-F CF₃ CH═CH-3-Pyridyl 624 5-F CF₃ CH═CH-4-Pyridyl 625 5-F CF₃ CH═CH-2-furanyl 626 5-F CF₃ CH═CH-3-furanyl 627 5-F CF₃ CH═CH-2-thienyl 628 5-F CF₃ CH═CH-3-thienyl 629 5-F CF₃ CH₂CH₂CH₂CH₂CH₃ 630 5-F CF₃ CH₂CH₂CH(CH₃)₂ 631 5-F CF₃ CH₂CH₂CH₂CH₃ 632 5-F CF₃ CH₂CH₂-cycPr 633 5-F CF₃ CH₂CH₂-tBu 634 5-F CF₃ CH₂CH₂CH₂CH₂OH 635 5-F CF₃ CH₂CH₂-CH(OH)Me 636 5-F CF₃ CH₂CH₂-Ph 637 5-F CF₃ CH₂CH₂-2-Pyridyl 638 5-F CF₃ CH₂CH₂-3-Pyridyl 639 5-F CF₃ CH₂CH₂-4-Pyridyl 640 5-F CF₃ CH₂CH₂-2-furanyl 641 5-F CF₃ CH₂CH₂-3-furanyl 642 5-F CF₃ CH₂CH₂-2-thienyl 643 5-F CF₃ CH₂CH₂-3-thienyl 644 5-Cl CF₃ C≡C-cycPr 645 5-Cl CF₃ C≡C-iPr 646 5-Cl CF₃ C≡C-nPr 647 5-Cl CF₃ C≡C-Bu 648 5-Cl CF₃ C≡C-iBu 649 5-Cl CF₃ C≡C-tBu 650 5-Cl CF₃ C≡C-Et 651 5-Cl CF₃ C≡C-Me 652 5-Cl CF₃ C≡OCH₂CH₂OH 653 5-Cl CF₃ C≡C-CH(OH)Me 654 5-Cl CF₃ C≡C-Ph 655 5-Cl CF₃ C≡C-(2-Cl)Ph 656 5-Cl CF₃ C≡C-(3-Cl)Ph 657 5-Cl CF₃ C≡C-(4-Cl)Ph 658 5-Cl CF₃ C≡C-(2-F)Ph 659 5-Cl CF₃ C≡C-(3-F)Ph 660 5-Cl CF₃ C≡C-(4-F)Ph 661 5-Cl CF₃ C≡C-(2-OH)Ph 662 5-Cl CF₃ C≡C-(3-OH)Ph 663 5-Cl CF₃ C≡C-(4-OH)Ph 664 5-Cl CF₃ C≡C-(2-OMe)Ph 665 5-Cl CF₃ C≡C-(3-OMe)Ph 666 5-Cl CF₃ C≡C-(4-OMe)Ph 667 5-Cl CF₃ C≡C-(2-CN)Ph 668 5-Cl CF₃ C≡C-(3-CN)Ph 669 5-Cl CF₃ C≡C-(4-CN)Ph 670 5-Cl CF₃ C≡C-(2-NO₂)Ph 671 5-Cl CF₃ C≡C-(3-NO₂)Ph 672 5-Cl CF₃ C≡C-(4-NO₂)Ph 673 5-Cl CF₃ C≡C-(2-NH₂)Ph 674 5-Cl CF₃ C≡C-(3-NH₂)Ph 675 5-Cl CF₃ C≡C-(4-NH₂)Ph 676 5-Cl CF₃ C≡C-(2-NMe₂)Ph 677 5-Cl CF₃ C≡C-(3-NMe₂)Ph 678 5-Cl CF₃ C≡C-(4-NMe₂)Ph 679 5-Cl CF₃ C≡C-2-Pyridyl 680 5-Cl CF₃ C≡C-3-Pyridyl 681 5-Cl CF₃ C≡C-4-Pyridyl 682 5-Cl CF₃ C≡C-2-furanyl 683 5-Cl CF₃ C≡C-3-furanyl 684 5-Cl CF₃ C≡C-2-thienyl 685 5-Cl CF₃ C≡C-3-thienyl 686 5-Cl CF₃ CH═CH-cycPr 687 5-Cl CF₃ CH═CH-iPr 688 5-Cl CF₃ CH═CH-nPr 689 5-Cl CF₃ CH═CH-Bu 690 5-Cl CF₃ CH═CH-iBu 691 5-Cl CF₃ CH═CH-tBu 692 5-Cl CF₃ CH═CH-Et 693 5-Cl CF₃ CH═CH-Me 694 5-Cl CF₃ CH═CH-Ph 695 5-Cl CF₃ CH═CH-2-Pyridyl 696 5-Cl CF₃ CH═CH-3-Pyridyl 697 5-Cl CF₃ CH═CH-4-Pyridyl 698 5-Cl CF₃ CH═CH-2-furanyl 699 5-Cl CF₃ CH═CH-3-furanyl 700 5-Cl CF₃ CH═CH-2-thienyl 701 5-Cl CF₃ CH═CH-3-thienyl 702 5-Cl CF₃ CH₂CH₂CH₂CH₂CH₃ 703 5-Cl CF₃ CH₂CH₂CH(CH₃)₂ 704 5-Cl CF₃ CH₂CH₂CH₂CH₃ 705 5-Cl CF₃ CH₂CH₂-cycPr 706 5-Cl CF₃ CH₂CH₂-tBu 707 5-Cl CF₃ CH₂CH₂CH₂CH₂OH 708 5-Cl CF₃ CH₂CH₂-CH(OH)Me 709 5-Cl CF₃ CH₂CH₂-Ph 710 5-Cl CF₃ CH₂CH₂-2-Pyridyl 711 5-Cl CF₃ CH₂CH₂-3-Pyridyl 712 5-Cl CF₃ CH₂CH₂-4-Pyridyl 713 5-Cl CF₃ CH₂CH₂-2-furanyl 714 5-Cl CF₃ CH₂CH₂-3-furanyl 715 5-Cl CF₃ CH₂CH₂-2-thienyl 716 5-Cl CF₃ CH₂CH₂-3-thienyl 717 6-OMe CF₃ C≡C-Bu 718 6-OMe CF₃ C≡C-iBu 719 6-OMe CF₃ C-C-tBu 720 6-OMe CF₃ C≡CCH₂CH₂OH 721 6-OMe CF₃ C≡C-CH(OH)Me 722 6-OMe CF₃ C≡C-Ph 723 6-OMe CF₃ C-C-(2-Cl)Ph 724 6-OMe CF₃ C≡C-(3-Cl)Ph 725 6-OMe CF₃ C≡C-(4-Cl)Ph 726 6-OMe CF₃ C≡C-(2-F)Ph 727 6-OMe CF₃ C≡C-(3-F)Ph 728 6-OMe CF₃ C≡C-(4-F)Ph 729 6-OMe CF₃ C≡C-(2-OH)Ph 730 6-OMe CF₃ C≡C-(3-OH)Ph 731 6-OMe CF₃ C≡C-(4-OH)Ph 732 6-OMe CF₃ C≡C-(2-OMe)Ph 733 6-OMe CF₃ C≡C-(3-OMe)Ph 734 6-OMe CF₃ C≡C-(4-OMe)Ph 735 6-OMe CF₃ C≡C-(2-CN)Ph 736 6-OMe CF₃ C≡C-(3-CN)Ph 737 6-OMe CF₃ C≡C-(4-CN)Ph 738 6-OMe CF₃ C≡C-(2-NO₂)Ph 739 6-OMe CF₃ C≡C-(3-NO₂)Ph 740 6-OMe CF₃ C≡C-(4-NO₂)Ph 741 6-OMe CF₃ C≡C-(2-NH₂)Ph 742 6-OMe CF₃ C≡C-(3-NH₂)Ph 743 6-OMe CF₃ C≡C-(4-NH₂)Ph 744 6-OMe CF₃ C≡C-(2-NMe₂)Ph 745 6-OMe CF₃ C≡C-(3-NMe₂)Ph 746 6-OMe CF₃ C≡C-(4-NMe₂)Ph 747 6-OMe CF₃ C≡C-2-Pyridyl 748 6-OMe CF₃ C≡C-3-Pyridyl 749 6-OMe CF₃ C≡C-4-Pyridyl 750 6-OMe CF₃ C≡C-2-furanyl 751 6-OMe CF₃ C≡C-3-furanyl 752 6-OMe CF₃ C≡C-2-thienyl 753 6-OMe CF₃ C≡C-3-thienyl 754 6-OMe CF₃ C≡C-2-oxazolyl 755 6-OMe CF₃ C≡C-2-thiazolyl 756 6-OMe CF₃ C≡C-4-isoxazolyl 757 6-OMe CF₃ C≡C-2-imidazolyl 758 6-OMe CF₃ CH₂C≡C-CH₃ 759 6-OMe CF₃ CH═CH-cycPr 760 6-OMe CF₃ CH═CH-iPr 761 6-OMe CF₃ CH═CH-nPr 762 6-OMe CF₃ CH═CH-Bu 763 6-OMe CF₃ CH═CH-iBu 764 6-OMe CF₃ CH═CH-tBu 765 6-OMe CF₃ CH═CH-Et 766 6-OMe CF₃ CH═CH-Me 767 6-OMe CF₃ CH═CH-Ph 768 6-OMe CF₃ CH═CH-2-Pyridyl 769 6-OMe CF₃ CH═CH-3-Pyridyl 770 6-OMe CF₃ CH═CH-4-Pyridyl 771 6-OMe CF₃ CH═CH-2-furanyl 772 6-OMe CF₃ CH═CH-3-furanyl 773 6-OMe CF₃ CH═CH-2-thienyl 774 6-OMe CF₃ CH═CH-3-thienyl 775 6-OMe CF₃ CH₂CH₂CH₂CH₂CH₃ 776 6-OMe CF₃ CH₂CH₂CH₃ 777 6-OMe CF₃ CH₂CH₂-cycPr 778 6-OMe CF₃ CH₂CH₂-tBu 779 6-OMe CF₃ CH₂CH₂CH₂CH₂OH 780 6-OMe CF₃ CH₂CH₂-CH(OH)Me 781 6-OMe CF₃ CH₂CH₂-(2-Cl)Ph 782 6-OMe CF₃ CH₂CH₂-(3-Cl)Ph 783 6-OMe CF₃ CH₂CH₂-(4-Cl)Ph 784 6-OMe CF₃ CH₂CH₂-(2-F)Ph 785 6-OMe CF₃ CH₂CH₂-(3-F)Ph 786 6-OMe CF₃ CH₂CH₂-(4-F)Ph 787 6-OMe CF₃ CH₂CH₂-(2-OH)Ph 788 6-OMe CF₃ CH₂CH₂-(3-OH)Ph 789 6-OMe CF₃ CH₂CH₂-(4-OH)Ph 790 6-OMe CF₃ CH₂CH₂-(2-OMe)Ph 791 6-OMe CF₃ CH₂CH₂-(3-OMe)Ph 792 6-OMe CF₃ CH₂CH₂-(4-OMe)Ph 793 6-OMe CF₃ CH₂CH₂-(2-CN)Ph 794 6-OMe CF₃ CH₂CH₂-(3-CN)Ph 795 6-OMe CF₃ CH₂CH₂-(4-CN)Ph 796 6-OMe CF₃ CH₂CH₂-(2-NO₂)Ph 797 6-OMe CF₃ CH₂CH₂-(3-NO₂)Ph 798 6-OMe CF₃ CH₂CH₂-(4-NO₂)Ph 799 6-OMe CF₃ CH₂CH₂-(2-NH₂)Ph 800 6-OMe CF₃ CH₂CH₂-(3-NH₂)Ph 801 6-OMe CF₃ CH₂CH₂-(4-NH₂)Ph 802 6-OMe CF₃ CH₂CH₂-(2- NMe₂)Ph 803 6-OMe CF₃ CH₂CH₂-(3- NMe₂) Ph 804 6-OMe CF₃ CH₂CH₂-(4- NMe₂) Ph 805 6-OMe CF₃ CH₂CH₂-2-Pyridyl 806 6-OMe CF₃ CH₂CH₂-3-Pyridyl 807 6-OMe CF₃ CH₂CH₂-4-Pyridyl 808 6-OMe CF₃ CH₂CH₂-2-furanyl 809 6-OMe CF₃ CH₂CH₂-3-furanyl 810 6-OMe CF₃ CH₂CH₂-2-thienyl 811 6-OMe CF₃ CH₂CH₂-3-thienyl 812 6-OMe CF₃ CH₂CH₂-2- oxazolyl 813 6-OMe CF₃ CH₂CH₂-2- thiazolyl 814 6-OMe CF₃ CH₂CH₂-4- isoxazolyl 815 6-OMe CF₃ CH₂CH₂-2- imidazolyl 816 6-OMe, 8-F CF₃ C≡C-iPr 817 6-OMe, 8-F CF₃ C≡C-nPr 818 6-OMe, 8-F CF_(3.) C≡C-Et 819 6-OMe, 8-F CF₃ C≡C-Me 820 6-OMe, 8-F CF₃ C≡C-Ph 821 6-OMe, 8-F CF₃ C≡C-2-Pyridyl 822 6-OMe, 8-F CF₃ C≡C-3-Pyridyl 823 6-OMe, 8-F CF₃ C≡C-4-Pyridyl 824 6-OMe, 8-F CF₃ C≡C-2-furanyl 825 6-OMe, 8-F CF₃ C≡C-3-furanyl 826 6-OMe, 8-F CF₃ C≡C-2-thienyl 827 6-OMe, 8-F CF₃ C≡C-3-thienyl 828 6-OMe, 8-F CF₃ CH═CH-cycPr 829 6-OMe, 8-F CF₃ CH═CH-iPr 830 6-OMe, 8-F CF₃ CH═CH-nPr 831 6-OMe, 8-F CF₃ CH═CH-Et 832 6-OMe, 8-F CF₃ CH═CH-Me 833 6-OMe, 8-F CF₃ CH═CH-Ph 834 6-OMe, 8-F CF₃ CH═CH-2-Pyridyl 835 6-OMe, 8-F CF₃ CH═CH-3-Pyridyl 836 6-OMe, 8-F CF₃ CH═CH-4-Pyridyl 837 6-OMe, 8-F CF₃ CH═CH-2-furanyl 838 6-OMe, 8-F CF₃ CH═CH-3-furanyl 839 6-OMe, 8-F CF₃ CH═CH-2-thienyl 840 6-OMe, 8-F CF₃ CH═CH-3-thienyl 841 6-OMe, 8-F CF₃ CH₂CH₂CH₂CH₂CH₃ 842 6-OMe, 8-F CF₃ CH₂CH₂CH(CH₃)₂ 843 6-OMe, 8-F CF₃ CH₂CH₂CH₂CH₃ 844 6-OMe, 8-F CF₃ CH₂CH₂-cycPr 845 6-OMe, 8-F CF₃ CH₂CH₂-Ph 846 6-OMe, 8-F CF₃ CH₂CH₂-2-Pyridyl 847 6-OMe, 8-F CF₃ CH₂CH₂-3-Pyridyl 848 6-OMe, 8-F CF₃ CH₂CH₂-4-Pyridyl 849 6-OMe, 8-F CF₃ CH₂CH₂-2-furanyl 850 6-OMe, 8-F CF₃ CH₂CH₂-3-furanyl 851 6-OMe, 8-F CF₃ CH₂CH₂-2-thienyl 852 6-OMe, 8-F CF₃ CH₂CH₂-3-thienyl 853 5-F, 6-OMe CF₃ C≡C-cycPr 854 5-F, 6-OMe CF₃ C≡C-iPr 855 5-F, 6-OMe CF₃ C≡C-nPr 856 5-F, 6-OMe CF₃ C≡C-Bu 857 5-F, 6-OMe CF₃ C≡C-iBu 858 5-F, 6-OMe CF₃ C≡C-tBu 859 5-F, 6-OMe CF₃ C≡C-Et 860 5-F, 6-OMe CF₃ C≡C-Me 861 5-F, 6-OMe CF₃ C≡C-Ph 862 5-F, 6-OMe CF₃ C≡C-(2-Cl)Ph 863 5-F, 6-OMe CF₃ C≡C-(3-Cl)Ph 864 5-F, 6-OMe CF₃ C≡C-(2-F)Ph 865 5-F, 6-OMe CF₃ C≡C-(3-F)Ph 866 5-F, 6-OMe CF₃ C≡C-(2-OH)Ph 867 5-F, 6-OMe CF₃ C≡C-(3-OH)Ph 868 5-F, 6-OMe CF₃ C≡C-(2-OMe)Ph 869 5-F, 6-OMe CF₃ C≡C-(3-OMe)Ph 870 5-F, 6-OMe CF₃ C≡C-(2-CN)Ph 871 5-F, 6-OMe CF₃ C≡C-(3-CN)Ph 872 5-F, 6-OMe CF₃ C≡C-(2-NH₂)Ph 873 5-F, 6-OMe CF₃ C≡C-(3-NH₂)Ph 874 5-F, 6-OMe CF₃ C≡C-(2-NMe₂)Ph 875 5-F, 6-OMe CF₃ C≡C-(3-NMe₂)Ph 876 5-F, 6-OMe CF₃ C≡C-2-Pyridyl 877 5-F, 6-OMe CF₃ C≡C-3-Pyridyl 878 5-F, 6-OMe CF₃ C≡C-4-Pyridyl 879 5-F, 6-OMe CF₃ C≡C-2-furanyl 880 5-F, 6-OMe CF₃ C≡C-3-furanyl 881 5-F, 6-OMe CF₃ C≡C-2-thienyl 882 5-F, 6-OMe CF₃ C≡C-3-thienyl 883 5-F, 6-OMe CF₃ CH═CH-cycPr 884 5-F, 6-OMe CF₃ CH═CH-iPr 885 5-F, 6-OMe CF₃ CH═CH-nPr 886 5-F, 6-OMe CF₃ CH═CH-Bu 887 5-F, 6-OMe CF₃ CH═CH-iBu 888 5-F, 6-OMe CF₃ CH═CH-tBu 889 5-F, 6-OMe CF₃ CH═CH-Et 890 5-F, 6-OMe CF₃ CH═CH-Me 891 5-F, 6-OMe CF₃ CH═CH-Ph 892 5-F, 6-OMe CF₃ CH═CH-2-Pyridyl 893 5-F, 6-OMe CF₃ CH═CH-3-Pyridyl 894 5-F, 6-OMe CF₃ CH═CH-4-Pyridyl 895 5-F, 6-OMe CF₃ CH═CH-2-furanyl 896 5-F, 6-OMe CF₃ CH═CH-3-furanyl 897 5-F, 6-OMe CF₃ CH═CH-2-thienyl 898 5-F, 6-OMe CF₃ CH═CH-3-thienyl 899 5-F, 6-OMe CF₃ CH₂CH₂CH₂CH₂CH₃ 900 5-F, 6-OMe CF₃ CH₂CH₂CH(CH₃)₂ 901 5-F, 6-OMe CF₃ CH₂CH₂CH₂CH₃ 902 5-F, 6-OMe CF₃ CH₂CH₂-cycPr 903 5-F, 6-OMe CF₃ CH₂CH₂-tBu 904 5-F, 6-OMe CF₃ CH₂CH₂-Ph 905 5-F, 6-OMe CF₃ CH₂CH₂-2-Pyridyl 906 5-F, 6-OMe CF₃ CH₂CH₂-3-Pyridyl 907 5-F, 6-OMe CF₃ CH₂CH₂-4-Pyridyl 908 5-F, 6-OMe CF₃ CH₂CH₂-2-furanyl 909 5-F, 6-OMe CF₃ CH₂CH₂-3-furanyl 910 5-F, 6-OMe CF₃ CH₂CH₂-2-thienyl 911 5-F, 6-OMe CF₃ CH₂CH₂-3-thienyl 912 6-NMe₂ CF₃ C≡C-nPr 913 6-NMe₂ CF₃ C≡C-Bu 914 6-NMe₂ CF₃ C≡C-iBu 915 6-NMe₂ CF₃ C≡C-tBu 916 6-NMe₂ CF₃ C≡C-Et 917 6-NMe₂ CF₃ C≡C-Me 918 6-NMe₂ CF₃ C≡C-Ph 919 6-NMe₂ CF₃ C≡C-(2-Cl)Ph 920 6-NMe₂ CF₃ C≡C-(3-Cl)Ph 921 6-NMe₂ CF₃ C≡C-(2-F)Ph 922 6-NMe₂ CF₃ C≡C-(3-F)Ph 923 6-NMe₂ CF₃ C≡C-(2-OH)Ph 924 6-NMe₂ CF₃ C≡C-(3-OH)Ph 925 6-NMe₂ CF₃ C≡C-(2-OMe)Ph 926 6-NMe₂ CF₃ C≡C-(3-OMe)Ph 927 6-NMe₂ CF₃ C≡C-(2-CN)Ph 928 6-NMe₂ CF₃ C≡C-(3-CN)Ph 929 6-NMe₂ CF₃ C≡C-(2-NH₂)Ph 930 6-NMe₂ CF₃ C≡C-(3-NH₂)Ph 931 6-NMe₂ CF₃ C≡C-(2-NMe₂)Ph 932 6-NMe₂ CF₃ C≡C-(3-NMe₂)Ph 933 6-NMe₂ CF₃ C≡C-2-Pyridyl 934 6-NMe₂ CF₃ C≡C-3-Pyridyl 935 6-NMe₂ CF₃ C≡C-4-Pyridyl 936 6-NMe₂ CF₃ C≡C-2-furanyl 937 6-NMe₂ CF₃ C≡C-3-furanyl 938 6-NMe₂ CF₃ C≡C-2-thienyl 939 6-NMe₂ CF₃ C≡C-3-thienyl 940 6-NMe₂ CF₃ CH═CH-cycPr 941 6-NMe₂ CF₃ CH═CH-iPr 942 6-NMe₂ CF₃ CH═CH-nPr 943 6-NMe₂ CF₃ CH═CH-Bu 944 6-NMe₂ CF₃ CH═CH-iBu 945 6-NMe₂ CF₃ CH═CH-tBu 946 6-NMe₂ CF₃ CH═CH-Et 947 6-NMe₂ CF₃ CH═CH-Me 948 6-NMe₂ CF₃ CH═CH-Ph 949 6-NMe₂ CF₃ CH═CH-2-Pyridyl 950 6-NMe₂ CF₃ CH═CH-3-Pyridyl 951 6-NMe₂ CF₃ CH═CH-4-Pyridyl 952 6-NMe₂ CF₃ CH═CH-2-furanyl 953 6-NMe₂ CF₃ CH═CH-3-furanyl 954 6-NMe₂ CF₃ CH═CH-2-thienyl 955 6-NMe₂ CF₃ CH═CH-3-thienyl 956 6-NMe₂ CF₃ CH₂CH₂CH₂CH₃ 957 6-NMe₂ CF₃ CH₂CH₂-cycPr 958 6-NMe₂ CF₃ CH₂CH₂-tBu 959 6-NMe₂ CF₃ CH₂CH₂-Ph 960 6-NMe₂ CF₃ CH₂CH₂-2-Pyridyl 961 6-NMe₂ CF₃ CH₂CH₂-3-Pyridyl 962 6-NMe₂ CF₃ CH₂CH₂-4-Pyridyl 963 6-NMe₂ CF₃ CH₂CH₂-2-furanyl 964 6-NMe₂ CF₃ CH₂CH₂-3-furanyl 965 6-NMe₂ CF₃ CH₂CH₂-2-thienyl 966 6-NMe₂ CF₃ CH₂CH₂-3-thienyl 967 6-COCH₃ CF₃ C≡C-iPr 968 6-COCH₃ CF₃ C≡C-nPr 969 6-COCH₃ CF₃ C≡C-Bu 970 6-COCH₃ CF₃ C≡C-iBu 971 6-COCH₃ CF₃ C≡C-tBu 972 6-COCH₃ CF₃ C≡C-Me 973 6-COCH₃ CF₃ C≡C-Ph 974 6-COCH₃ CF₃ C≡C-(2-Cl)Ph 975 6-COCH₃ CF₃ C≡C-(3-Cl)Ph 976 6-COCH₃ CF₃ C≡C-(2-F)Ph 977 6-COCH₃ CF₃ C≡C-(3-F)Ph 978 6-COCH₃ CF₃ C≡C-(2-OH)Ph 979 6-COCH₃ CF₃ C≡C-(3-OH)Ph 980 6-COCH₃ CF₃ C≡C-(2-OMe)Ph 981 6-COCH₃ CF₃ C≡C-(3-OMe)Ph 982 6-COCH₃ CF₃ C≡C-(2-CN)Ph 983 6-COCH₃ CF₃ C≡C-(3-CN)Ph 984 6-COCH₃ CF₃ C≡C-(2-NH₂)Ph 985 6-COCH₃ CF₃ C≡C-(3-NH₂)Ph 986 6-COCH₃ CF₃ C≡C-(2-NMe₂)Ph 987 6-COCH₃ CF₃ C≡C-(3-NMe₂)Ph 988 6-COCH₃ CF₃ C≡C-2-Pyridyl 989 6-COCH₃ CF₃ C≡C-3-Pyridyl 990 6-COCH₃ CF₃ C≡C-4-Pyridyl 991 6-COCH₃ CF₃ C≡C-2-furanyl 992 6-COCH₃ CF₃ C≡C-3-furanyl 993 6-COCH₃ CF₃ C≡C-2-thienyl 994 6-COCH₃ CF₃ C≡C-3-thienyl 995 6-COCH₃ CF₃ CH═CH-cycPr 996 6-COCH₃ CF₃ CH═CH-iPr 997 6-COCH₃ CF₃ CH═CH-nPr 998 6-COCH₃ CF₃ CH═CH-Bu 999 6-COCH₃ CF₃ CH═CH-iBu 1000  6-COCH₃ CF₃ CH═CH-tBu 1001  6-COCH₃ CF₃ CH═CH-Et 1002  6-COCH₃ CF₃ CH═CH-Me 1003  6-COCH₃ CF₃ CH═CH-Ph 1004  6-COCH₃ CF₃ CH═CH-2-Pyridyl 1005  6-COCH₃ CF₃ CH═CH-3-Pyridyl 1006  6-COCH₃ CF₃ CH═CH-4-Pyridyl 1007  .6-COCH₃ CF₃ CH═CH-2-furanyl 1008  6-COCH₃ CF₃ CH═CH-3-furanyl 1009  6-COCH₃ CF₃ CH═CH-2-thienyl 1010  6-COCH₃ CF₃ CH═CH-3-thienyl 1011  6-COCH₃ CF₃ CH₂CH₂CH₂CH₂CH₃ 1012  6-COCH₃ CF₃ CH₂CH₂CH(CH₃)₂ 1013  6-COCH₃ CF₃ CH₂CH₂CH₂CH₃ 1014  6-COCH₃ CF₃ CH₂CH₂-cycPr 1015  6-COCH₃ CF₃ CH₂CH₂-tBu 1016  6-COCH₃ CF₃ CH₂CH₂-Ph 1017  6-COCH₃ CF₃ CH₂CH₂-2-Pyridyl 1018  6-COCH₃ CF₃ CH₂CH₂-3-Pyridyl 1019  6-COCH₃ CF₃ CH₂CH₂-4-Pyridyl 1020  6-COCH₃ CF₃ CH₂CH₂-2-furanyl 1021  6-COCH₃ CF₃ CH₂CH₂-3-furanyl 1022  6-COCH₃ CF₃ CH₂CH₂-2-thienyl 1023  6-COCH₃ CF₃ CH₂CH₂-3-thienyl 1024  6-CH₃ CF₃ C≡C-nPr 1025  6-CH₃ CF₃ C≡C-Bu 1026  6-CH₃ CF₃ C≡C-iBu 1027  6-CH₃ CF₃ C≡C-tBu 1028  6-CH₃ CF₃ C≡C-Me 1029  6-CH₃ CF₃ C≡C-Ph 1030  6-CH₃ CF₃ C≡C-(2-Cl)Ph 1031  6-CH₃ CF₃ C≡C-(3-Cl)Ph 1032  6-CH₃ CF₃ C≡C-(2-F)Ph 1033  6-CH₃ CF₃ C≡C-(3-F)Ph 1034  6-CH₃ CF₃ C≡C-(2-OH)Ph 1035  6-CH₃ CF₃ C≡C-(3-OH)Ph 1036  6-CH₃ CF₃ C≡C-(2-OMe)Ph 1037  6-CH₃ CF₃ C≡C-(3-OMe)Ph 1038  6-CH₃ CF₃ C≡C-(2-CN)Ph 1039  6-CH₃ CF₃ C≡C-(3-CN)Ph 1040  6-CH₃ CF₃ C≡C-(2-NH₂)Ph 1041  6-CH₃ CF₃ C≡C-(3-NH₂)Ph 1042  6-CH₃ CF₃ C≡C-(2-NMe₂)Ph 1043  6-CH₃ CF₃ C≡C-(3-NMe₂)Ph 1044  6-CH₃ CF₃ C≡C-2-Pyridyl 1045  6-CH₃ CF₃ C≡C-3-Pyridyl 1046  6-CH₃ CF₃ C≡C-4-Pyridyl 1047  6-CH₃ CF₃ C≡C-2-furanyl 1048  6-CH₃ CF₃ C≡C-3-furanyl 1049  6-CH₃ CF₃ C≡C-2-thienyl 1050  6-CH₃ CF₃ C≡C-3-thienyl 1051  6-CH₃ CF₃ CH═CH-cycPr 1052  6-CH₃ CF₃ CH═CH-iPr 1053  6-CH₃ CF₃ CH═CH-nPr 1054  6-CH₃ CF₃ CH═CH-Bu 1055  6-CH₃ CF₃ CH═CH-iBu 1056  6-CH₃ CF₃ CH═CH-tBu 1057  6-CH₃ CF₃ CH═CH-Et 1058  6-CH₃ CF₃ CH═CH-Me 1059  6-CH₃ CF₃ CH═CH-Ph 1060  6-CH₃ CF₃ CH═CH-2-Pyridyl 1061  6-CH₃ CF₃ CH═CH-3-Pyridyl 1062  6-CH₃ CF₃ CH═CH-4-Pyridyl 1063  6-CH₃ CF₃ CH═CH-2-furanyl 1064  6-CH₃ CF₃ CH═CH-3-furanyl 1065  6-CH₃ CF₃ CH═CH-2-thienyl 1066  6-CH₃ CF₃ CH═CH-3-thienyl 1067  6-CH₃ CF₃ CH₂CH₂CH₂CH₂CH₃ 1068  6-CH₃ CF₃ CH₂CH₂CH(CH₃)₂ 1069  6-CH₃ CF₃ CH₂CH₂CH₂CH₃ 1070  6-CH₃ CF₃ CH₂CH₂-cycPr 1071  6-CH₃ CF₃ CH₂CH₂-tBu 1072  6-CH₃ CF₃ CH₂CH₂-Ph 1073  6-CH₃ CF₃ CH₂CH₂-2-Pyridyl 1074  6-CH₃ CF₃ CH₂CH₂-3-Pyridyl 1075  6-CH₃ CF₃ CH₂CH₂-4-Pyridyl 1076  6-CH₃ CF₃ CH₂CH₂-2-furanyl 1077  6-CH₃ CF₃ CH₂CH₂-3-furanyl 1078  6-CH₃ CF₃ CH₂CH₂-2-thienyl 1079  6-CH₃ CF₃ CH₂CH₂-3-thienyl 1080  6,8-diCl CF₃ C≡C-iPr 1081  6,8-diCl CF₃ C≡C-nPr 1082  6,8-diCl CF₃ C≡C-Et 1083  6,8-diCl CF₃ C≡C-Me 1084  6,8-diCl CF₃ C≡C-Ph 1085  6,8-diCl CF₃ C≡C-2-Pyridyl 1086  6,8-diCl CF₃ C≡C-3-Pyridyl 1087  6,8-diCl CF₃ C≡C-4-Pyridyl 1088  6,8-diCl CF₃ C≡C-2-furanyl 1089  6,8-diCl CF₃ C≡C-3-furanyl 1090  6,8-diCl CF₃ C≡C-2-thienyl 1091  6,8-diCl CF₃ C≡C-3-thienyl 1092  6,8-diCl CF₃ CH═CH-cycPr 1093  6,8-diCl CF₃ CH═CH-iPr 1094  6,8-diCl CF₃ CH═CH-nPr 1095  6,8-diCl CF₃ CH═CH-Et 1096  6,8-diCl CF₃ CH═CH-Me 1097  6,8-diCl CF₃ CH═CH-Ph 1098  6,8-diCl CF₃ CH═CH-2-Pyridyl 1099  6,8-diCl CF₃ CH═CH-3-Pyridyl 1100  6,8-diCl CF₃ CH═CH-4-Pyridyl 1101  6,8-diCl CF₃ CH═CH-2-furanyl 1102  6,8-diCl CF₃ CH═CH-3-furanyl 1103  6,8-diCl CF₃ CH═CH-2-thienyl 1104  6,8-diCl CF₃ CH═CH-3-thienyl 1105  6,8-diCl CF₃ CH₂CH₂CH₂CH₂CH₃ 1106  6,8-diCl CF₃ CH₂CH₂CH(CH₃)₂ 1107  6,8-diCl CF₃ CH₂CH₂CH₂CH₃ 1108  6,8-diCl CF₃ CH₂CH₂-cycPr 1109  6,8-diCl CF₃ CH₂CH₂-2-Pyridyl 1110  6,8-diCl CF₃ CH₂CH₂-3-Pyridyl 1111  6,8-diCl CF₃ CH₂CH₂-4-Pyridyl 1112  6,8-diCl CF₃ CH₂CH₂-2-furanyl 1113  6,8-diCl CF₃ CH₂CH₂-3-furanyl 1114  6,8-diCl CF₃ CH₂CH₂-2-thienyl 1115  6,8-diCl CF₃ CH₂CH₂-3-thienyl 1116  5,6,8-triF CF₃ C≡C-Me 1117  5,6,8-triF CF₃ C≡C-Ph 1118  5,6,8-triF CF₃ C≡C-2-Pyridyl 1119  5,6,8-triF CF₃ C≡C-3-Pyridyl 1120  5,6,8-triF CF₃ C≡C-4-Pyridyl 1121  5,6,8-triF CF₃ C≡C-2-furanyl 1122  5,6,8-triF CF₃ C≡C-3-furanyl 1123  5,6,8-triF CF₃ C≡C-2-thienyl 1124  5,6,8-triF CF₃ C≡C-3-thienyl 1125  5,6,8-triF CF₃ CH═CH-cycPr 1126  5,6,8-triF CF₃ CH═CH-iPr 1127  5,6,8-triF CF₃ CH═CH-nPr 1128  5,6,8-triF CF₃ CH═CH-Et 1129  5,6,8-triF CF₃ CH═CH-Me 1130  5,6,8-triF CF₃ CH═CH-Ph 1131  5,6,8-triF CF₃ CH═CH-2-Pyridyl 1132  5,6,8-triF CF₃ CH═CH-3-Pyridyl 1133  5,6,8-triF CF₃ CH═CH-4-Pyridyl 1134  5,6,8-triF CF₃ CH═CH-2-furanyl 1135  5,6,8-triF CF₃ CH═CH-3-furanyl 1136  5,6,8-triF CF₃ CH═CH-2-thienyl 1137  5,6,8-triF CF₃ CH═CH-3-thienyl 1138  5,6,8-triF CF₃ CH₂CH₂CH₂CH₂CH₃ 1139  5,6,8-triF CF₃ CH₂CH₂CH(CH₃)₂ 1140  5,6,8-triF CF₃ CH₂CH₂CH₂CH₃ 1141  5,6,8-triF CF₃ CH₂CH₂-cycPr 1142  5,6,8-triF CF₃ CH₂CH₂-Ph 1143  5,6,8-triF CF₃ CH₂CH₂-2-Pyridyl 1144  5,6,8-triF CF₃ CH₂CH₂-3-Pyridyl 1145  5,6,8-triF CF₃ CH₂CH₂-4-Pyridyl 1146  5,6,8-triF CF₃ CH₂CH₂-2-furanyl 1147  5,6,8-triF CF₃ CH₂CH₂-3-furanyl 1148  5,6,8-triF CF₃ CH₂CH₂-2-thienyl 1149  5,6,8-triF CF₃ CH₂CH₂-3-thienyl 1150  5,8-diF CF₃ C≡C-Me 1151  5,8-diF CF₃ C≡C-Ph 1152  5,8-diF CF₃ C≡C-2-Pyridyl 1153  5,8-diF CF₃ C≡C-3-Pyridyl 1154  5,8-diF CF₃ C≡C-4-Pyridyl 1155  5,8-diF CF₃ C≡C-2-furanyl 1156  5,8-diF CF₃ C≡C-3-furanyl 1157  5,8-diF CF₃ C≡C-2-thienyl 1158  5,8-diF CF₃ C≡C-3-thienyl 1159  5,8-diF CF₃ CH═CH-cycPr 1160  5,8-diF CF₃ CH═CH-iPr 1161  5,8-diF CF₃ CH═CH-nPr 1162  5,8-diF CF₃ CH═CH-Et 1163  5,8-diF CF₃ CH═CH-Me 1164  5,8-diF CF₃ CH═CH-Ph 1165  5,8-diF CF₃ CH═CH-2-Pyridyl 1166  5,8-diF CF₃ CH═CH-3-Pyridyl 1167  5,8-diF CF₃ CH═CH-4-Pyridyl 1168  5,8-diF CF₃ CH═CH-2-furanyl 1169  5,8-diF CF₃ CH═CH-3-furanyl 1170  5,8-diF CF₃ CH═CH-2-thienyl 1171  5,8-diF CF₃ CH═CH-3-thienyl 1172  5,8-diF CF₃ CH₂CH₂CH₂CH₂CH₃ 1173  5,8-diF CF₃ CH₂CH₂CH(CH₃)₂ 1174  5,8-diF CF₃ CH₂CH₂CH₂CH₃ 1175  5,8-diF CF₃ CH₂CH₂-cycPr 1176  5,8-diF CF₃ CH₂CH₂-Ph 1177  5,8-diF CF₃ CH₂CH₂-2-Pyridyl 1178  5,8-diF CF₃ CH₂CH₂-3-Pyridyl 1179  5,8-diF CF₃ CH₂CH₂-4-Pyridyl 1180  5,8-diF CF₃ CH₂CH₂-2-furanyl 1181  5,8-diF CF₃ CH-CH₂-3-furanyl 1182  5,8-diF CF₃ CH₂CH₂-2-thienyl 1183  5,8-diF CF₃ CH₂CH₂-3-thienyl 1184  6-iPr CF₃ C≡C-nPr 1185  6-iPr CF₃ C≡C-Et 1186  6-iPr CF₃ C≡C-Me 1187  6-iPr CF₃ C≡C-3-Pyridyl 1188  6-iPr CF₃ C≡C-2-furanyl 1189  6-iPr CF₃ C≡C-3-furanyl 1190  6-iPr CF₃ C≡C-2-thienyl 1191  6-iPr CF₃ C≡C-3-thienyl 1192  6-iPr CF₃ CH═CH-cycPr 1193  6-iPr CF₃ CH═CH-iPr 1194  6-iPr CF₃ CH═CH-nPr 1195  6-iPr CF₃ CH═CH-Et 1196  6-iPr CF₃ CH═CH-Me 1197  6-iPr CF₃ CH═CH-Ph 1198  6-iPr CF₃ CH═CH-2-furanyl 1199  6-iPr CF₃ CH═CH-3-furanyl 1200  6-iPr CF₃ CH═CH-2-thienyl 1201  6-iPr CF₃ CH═CH-3-thienyl 1202  6-iPr CF₃ CH₂CH₂CH₂CH₃ 1203  6-iPr CF₃ CH₂CH₂-cycPr 1204  6-OCF₃ CF₃ C≡C-nPr 1205  6-OCF₃ CF₃ C≡C-Et 1206  6-OCF₃ CF₃ C≡C-Me 1207  6-OCF₃ CF₃ C≡C-3-Pyridyl 1208  6-OCF₃ CF₃ C≡C-2-furanyl 1209  6-OCF₃ CF₃ C≡C-3-furanyl 1210  6-OCF₃ CF₃ C≡C-2-thienyl 1211  6-OCF₃ CF₃ C≡C-3-thienyl 1212  6-OCF₃ CF₃ CH═CH-cycPr 1213  6-OCF₃ CF₃ CH═CH-iPr 1214  6-OCF₃ CF₃ CH═CH-nPr 1215  6-OCF₃ CF₃ CH═CH-Et 1216  6-OCF₃ CF₃ CH═CH-Me 1217  6-OCF₃ CF₃ CH═CH-Ph 1218  6-OCF₃ CF₃ CH═CH-3-Pyridyl 1219  6-OCF₃ CF₃ CH═CH-2-furanyl 1220  6-OCF₃ CF₃ CH═CH-3-furanyl 1221  6-OCF₃ CF₃ CH═CH-2-thienyl 1222  6-OCF₃ CF₃ CH═CH-3-thienyl 1223  6-OCF₃ CF₃ CH₂CH₂CH₂CH₃ 1224  6-OCF₃ CF₃ CH₂CH₂-cycPr 1225  6-(pyrazol- CF₃ C≡C-cycPr 5-yl) 1226  6-(pyrazol- CF₃ C≡C-iPr 5-yl) 1227  6-(pyrazol- CF₃ C≡C-nPr 5-yl) 1228  6-(pyrazol- CF₃ C≡C-Et 5-yl) 1229  6-(pyrazol- CF₃ C≡C-Me 5-yl) 1230  6-(pyrazol- CF₃ C≡C-Ph 5-yl) 1231  6-(pyrazol- CF₃ C≡C-3-Pyridyl 5-yl) 1232  6-(pyrazol- CF₃ C≡C-2-furanyl 5-yl) 1233  6-(pyrazol- CF₃ C≡C-3-furanyl 5-yl) 1234  6-(pyrazol- CF₃ C≡C-2-thienyl 5-yl) 1235  6-(pyrazol- CF₃ C≡C-3-thienyl 5-yl) 1236  6-(pyrazol- CF₃ CH═CH-cycPr 5-yl) 1237  6-(pyrazol- CF₃ CH═CH-iPr 5-yl) 1238  6-(pyrazol- CF₃ CH═CH-nPr 5-yl) 1239  6-(pyrazol- CF₃ CH═CH-Et 5-yl) 1240  6-(pyrazol- CF₃ CH═CH-Me 5-yl) 1241  6-(pyrazol- CF₃ CH═CH-Ph 5-yl) 1242  6-(pyrazol- CF₃ CH═CH-3-Pyridyl 5-yl) 1243  6-(pyrazol- CF₃ CH═CH-2-furanyl 5-yl) 1244  6- (pyrazol- CF₃ CH═CH-3-furanyl 5-yl) 1245  6-(pyrazol- CF₃ CH═CH-2-thienyl 5-yl) 1246  6- (pyrazol- CF₃ CH═CH-3-thienyl 5-yl) 1247  6-(pyrazol- CF₃ Pentyl 5-yl) 1248  6-(pyrazol- CF₃ CH₂CH₂-iPr 5-yl) 1249  6-(pyrazol- CF₃ CH₂CH₂CH₂CH₃ 5-yl) 1250  6-(pyrazol- CF₃ CH₂CH₂-cycPr 5-yl) 1251  H CF₃ C≡C-nPr 1252  H CF₃ C≡C-Et 1253  H CF₃ C≡C-Me 1254  H CF₃ C≡C-3-Pyridyl 1255  H CF₃ C-C-2-furanyl 1256  H CF₃ C-C-3-furanyl 1257  H CF₃ C≡C-2-thienyl 1258  H CF₃ C≡C-3-thienyl 1259  H CF₃ CH═CH-cycPr 1260  H CF₃ CH═CH-iPr 1261  H CF₃ CH═CH-nPr 1262  H CF₃ CH═CH-Et 1263  H CF₃ CH═CH-Me 1264  H CF₃ CH═CH-Ph 1265  H CF₃ CH═CH-3-Pyridyl 1266  H CF₃ CH═CH-2-furanyl 1267  H CF₃ CH═CH-3-furanyl 1268  H CF₃ CH═CH-2-thienyl 1269  H CF₃ CH═CH-3-thienyl 1270  H CF₃ CH₂CH₂CH₂CH₃ 1271  H CF₃ CH₂CH₂-cycPr 1272  6-Ph CF₃ C≡C-Me 1273  6-Ph CF₃ C≡C-Ph 1274  6-Ph CF₃ C-C-3-Pyridyl 1275  6-Ph CF₃ C≡C-2-furanyl 1276  6-Ph CF₃ C≡C-3-furanyl 1277  6-Ph CF₃ C≡C-2-thienyl 1278  6-Ph CF₃ C≡C-3-thienyl 1279  6-Ph CF₃ CH═CH-cycPr 1280  6-Ph CF₃ CH═CH-iPr 1281  6-Ph CF₃ CH═CH-nPr 1282  6-Ph CF₃ CH═CH-Et 1283  6-Ph CF₃ CH═CH-Me 1284  6-Ph CF₃ CH═CH-Ph 1285  6-Ph CF₃ CH═CH-3-Pyridyl 1286  6-Ph CF₃ CH═CH-2-furanyl 1287  6-Ph CF₃ CH═CH-3-furanyl 1288  6-Ph CF₃ CH═CH-2-thienyl 1289  6-Ph CF₃ CH═CH-3-thienyl 1290  6-Ph CF₃ Pentyl 1291  6-Ph CF₃ CH₂CH₂CH₂CH₃ 1292  6-Ph CF₃ CH₂CH₂-cycPr 1293  6-CN CF₃ C≡C-cycPr 1294  6-CN CF₃ C≡C-iPr 1295  6-CN CF₃ C≡C-nPr 1296  6-CN CF₃ C≡C-Et 1297  6-CN CF₃ C≡C-3-Pyridyl 1298  6-CN CF₃ C≡C-2-furanyl 1299  6-CN CF₃ C≡C-3-furanyl 1300  6-CN CF₃ C≡C-2-thienyl 1301  6-CN CF₃ C≡C-3-thienyl 1302  6-CN CF₃ CH═CH-cycPr 1303  6-CN CF₃ CH═CH-iPr 1304  6-CN CF₃ CH═CH-nPr 1305  6-CN CF₃ CH═CH-Et 1306  6-CN CF₃ CH═CH-3-Pyridyl 1307  6-CN CF₃ CH═CH-2-furanyl 1308  6-CN CF₃ CH═CH-3-furanyl 1309  6-CN CF₃ CH═CH-2-thienyl 1310  6-CN CF₃ CH═CH-3-thienyl 1311  6-NO₂ CF₃ C≡C-cycPr 1312  6-NO₂ CF₃ C≡C-iPr 1313  6-NO₂ CF₃ C≡C-nPr 1314  6-NO₂ CF₃ C≡C-Et 1315  6-NO₂ CF₃ C≡C-3-Pyridyl 1316  6-NO₂ CF₃ C≡C-2-furanyl 1317  6-NO₂ CF₃ C≡C-3-furanyl 1318  6-NO₂ CF₃ C≡C-2-thienyl 1319  6-NO₂ CF₃ C≡C-3-thienyl 1320  6-NHMe CF₃ C≡C-cycPr 1321  6-NHMe CF₃ C≡C-iPr 1322  6-NHMe CF₃ C≡C-nPr 1323  6-NHMe CF₃ C≡C-Et 1324  6-NHMe CF₃ C≡C-3-Pyridyl 1325  6-NHMe CF₃ C≡C-2-furanyl 1326  6-NHMe CF₃ C≡C-3-furanyl 1327  6-NHMe CF₃ C≡C-2-thienyl 1328  6-NHMe CF₃ C≡C-3-thienyl 1329  6-NHMe CF₃ CH═CH-cycPr 1330  6-NHMe CF₃ CH═CH-iPr 1331  6-NHMe CF₃ CH═CH-nPr 1332  6-NHMe CF₃ CH═CH-Et 1333  6-NHMe CF₃ CH═CH-3-Pyridyl 1334  6-NHMe CF₃ CH═CH-2-furanyl 1335  6-NHMe CF₃ CH═CH-3-furanyl 1336  6-NHMe CF₃ CH═CH-2-thienyl 1337  6-NHMe CF₃ CH═CH-3-thienyl 1338  6,7-OCH₂O— CF₃ C≡C-cycPr 1339  6,7-OCH₂O— CF₃ C≡C-iPr 1340  6,7-OCH₂O— CF₃ C≡C-nPr 1341  6,7-OCH₂O— CF₃ C≡C-Et 1342  6,7-OCH₂O— CF₃ C≡C-3-Pyridyl 1343  6,7-OCH₂O— CF₃ C≡C-2-furanyl 1344  6,7-OCH₂O— CF₃ C≡C-3-furanyl 1345  6,7-OCH₂O— CF₃ C≡C-2-thienyl 1346  6,7-OCH₂O— CF₃ C≡C-3-thienyl 1347  6,7-diCl CF₃ C≡C-cycPr 1348  6,7-diCl CF₃ C≡C-iPr 1349  6,7-diCl CF₃ C≡C-nPr 1350  6,7-diCl CF₃ C≡C-Et 1351  6,7-diCl CF₃ C≡C-3-Pyridyl 1352  6,7-diCl CF₃ C≡C-2-furanyl 1353  6,7-diCl CF₃ C≡C-3-furanyl 1354  6,7-diCl CF₃ C≡C-2-thienyl 1355  6,7-diCl CF₃ C≡C-3-thienyl 1356  7-Cl CF₃ C≡C-cycPr 1357  7-Cl CF₃ C≡C-iPr 1358  7-Cl CF₃ C≡C-nPr 1359  7-Cl CF₃ C≡C-Et 1360  7-Cl CF₃ C≡C-3-Pyridyl 1361  7-Cl CF₃ C≡C-2-furanyl 1362  7-Cl CF₃ C≡C-3-furanyl 1363  7-Cl CF₃ C≡C-2-thienyl 1364  7-Cl CF₃ C≡C-3-thienyl *Unless otherwise noted, stereochemistry is (+/−).

TABLE 3

Ex. # G R¹ R² 1401 6-Cl, 8-F cycPr C≡C-cycPr 1402 6-Cl, 8-F cycPr C≡C-iPr 1403 6-Cl, 8-F cycPr C≡C-nPr 1404 6-Cl, 8-F cycPr C≡C—Et 1405 6-Cl, 8-F cycPr C≡C-3-Pyridyl 1406 6-Cl, 8-F cycPr C≡C-2-furanyl 1407 6-Cl, 8-F cycPr C≡C-3-furanyl 1408 6-Cl, 8-F cycPr C≡C-2-thienyl 1409 6-Cl, 8-F cycPr C≡C-3-thienyl 1410 6-Cl, 8-F iPr C≡C-cycPr 1411 6-Cl, 8-F iPr C≡C-iPr 1412 6-Cl, 8-F iPr C≡C-nPr 1413 6-Cl, 8-F iPr C≡C—Et 1414 6-Cl, 8-F iPr C≡C-3-Pyridyl 1415 6-Cl, 8-F iPr C≡C-2-furanyl 1416 6-Cl, 8-F iPr C≡C-3-furanyl 1417 6-Cl, 8-F iPr C≡C-2-thienyl 1418 6-Cl, 8-F iPr C≡C-3-thienyl 1419 6-Cl, 8-F Et C≡C-cycPr 1420 6-Cl, 8-F Et C≡C-iPr 1421 6-Cl, 8-F Et C≡C-nPr 1422 6-Cl, 8-F Et C≡C—Et 1423 5,6-diF cycPr C≡C-cycPr 1424 5,6-diF cycPr C≡C-iPr 1425 5,6-diF cycPr C≡C-nPr 1426 5,6-diF cycPr C≡C—Et 1427 5,6-diF cycPr C≡C-3-Pyridyl 1428 5,6-diF cycPr C≡C-2-furanyl 1429 5,6-diF cycPr C≡C-3-furanyl 1430 5,6-diF cycPr C≡C-2-thienyl 1431 5,6-diF cycPr C≡C-3-thienyl 1432 5,6-diF iPr C≡C-cycPr 1433 5,6-diF iPr C≡C-iPr 1434 5,6-diF iPr C≡C-nPr 1435 5,6-diF iPr C≡C—Et 1436 5,6-diF iPr C≡C-3-Pyridyl 1437 5,6-diF iPr C≡C-2-furanyl 1438 5,6-diF iPr C≡C-3-furanyl 1439 5,6-diF iPr C≡C-2-thienyl 1440 5,6-diF iPr C≡C-3-thienyl 1441 5,6-diF Et C≡C-cycPr 1442 5,6-diF Et C≡C-iPr 1443 5,6-diF Et C≡C-nPr 1444 5,6-diF Et C≡C—Et 1445 5,6-diCl cycPr C≡C-cycPr 1446 5,6-diCl cycPr C≡C-iPr 1447 5,6-diCl cycPr C≡C-nPr 1448 5,6-diCl cycPr C≡C—Et 1449 5,6-diCl cycPr C≡C-3-Pyridyl 1450 5,6-diCl cycPr C≡C-2-furanyl 1451 5,6-diCl cycPr C≡C-3-furanyl 1452 5,6-diCl cycPr C≡C-2-thienyl 1453 5,6-diCl cycPr C≡C-3-thienyl 1454 5,6-diCl iPr C≡C-cycPr 1455 5,6-diCl iPr C≡C-iPr 1456 5,6-diCl iPr C≡C-nPr 1457 5,6-diCl iPr C≡C—Et 1458 5,6-diCl iPr C≡C-3-Pyridyl 1459 5,6-diCl iPr C≡C-2-furanyl 1460 5,6-diCl iPr C≡C-3-furanyl 1461 5,6-diCl iPr C≡C-2-thienyl 1462 5,6-diCl iPr C≡C-3-thienyl 1463 5,6-diCl Et C≡-C-cycPr 1464 5,6-diCl Et C≡-C-iPr 1465 5,6-diCl Et C≡C-nPr 1466 5,6-diCl Et C≡C—Et 1467 5-Cl, 6-F cycPr C≡-C-cycPr 1468 5-Cl, 6-F cycPr C≡C-iPr 1469 5-Cl, 6-F cycPr C≡C-nPr 1470 S-Cl, 6-F cycPr C-≡C—Et 1471 5-Cl, 6-F cycFr C≡-C-3-Pyridyl 1472 5-Cl, 6-F cycPr C≡-C-2-furanyl 1473 5-Cl, 6-F cycPr C≡C-3-furanyl 1474 5-Cl, 6-F cycPr C≡C-2-thienyl 1475 5-Cl, 6-F cycPr C≡-C-3-thienyl 1476 5-Cl, 6-F iPr C≡C-cycPr 1477 5-Cl, 6-F iPr C≡C-iPr 1478 5-Cl, 6-F iPr C≡C-nPr 1479 5-Cl, 6-F iPr C≡C—Et 1480 5-Cl, 6-F iPr C≡C-3-Pyridyl 1481 5-Cl, 6-F iPr C≡C-2-furanyl 1482 5-Cl, 6-F iPr C≡C-3-furanyl 1483 5-Cl, 6-F iPr C≡C-2-thienyl 1484 5-Cl, 6-F iPr C≡C-3-thienyl 1485 5-Cl, 6-F Et C≡C-cycPr 1486 5-Cl, 6-F Et C≡C-iPr 1487 5-Cl, 6-F Et C≡C-nPr 1488 5-Cl, 6-F Et C≡C—Et 1489 5,6-OCH₂O— cycPr C≡C-cycPr 1490 5,6-OCH₂O— cycPr C≡C-iPr 1491 5,6-OCH₂O— cycPr C≡C-nPr 1492 5,6-OCH₂O— cycPr C≡C—Et 1493 5,6-OCH₂O— cycPr C≡C-3-Pyridyl 1494 5,6-OCH₂O— cycPr C≡C-2-furanyl 1495 5,6-OCH₂O— cycPr C≡C-3-furanyl 1496 5,6-OCH₂O— cycPr C≡C-2-thienyl 1497 5,6-OCH₂O— cycPr C≡C-3-thienyl 1498 5,6-OCH₂O— iPr C≡C-cycPr 1499 5,6-OCH₂O— iPr C≡C-iPr 1500 5,6-OCH₂O— iPr C≡C-nPr 1501 5,6-OCH₂O— iPr C≡C—Et 1502 5,6-OCH₂O— iPr C≡C-3-Pyridyl 1503 5,6-OCH₂O— iPr C≡C-2-furanyl 1504 5,6-OCH₂O— iPr C≡C-3-furanyl 1505 5,6-OCH₂O— iPr C≡C-2-thienyl 1506 5,6-OCH₂O— iPr C≡C-3-thienyl 1507 5,6-OCH₂O— Et C≡C-cycPr 1508 5,6-OCH₂O— Et C≡C-iPr 1509 5,6-OCH₂O— Et C≡C-nPr 1510 5,6-OCH₂O— Et C≡C—Et 1511 5-F cycPr C≡C-cycPr 1512 5-F cycPr C≡C-iPr 1513 5-F cycPr C≡C-nPr 1514 5-F cycPr C≡C—Et 1515 5-F cycPr C≡C-3-Pyridyl 1516 5-F cycPr C≡C-2-furanyl 1517 5-F cycPr C≡C-3-furanyl 1518 5-F cycPr C≡C-2-thienyl 1519 5-F cycPr C≡C-3-thienyl 1520 5-F iPr C≡C-cycPr 1521 5-F iPr C≡C-iPr 1522 5-F iPr C≡C-nPr 1523 5-F iPr C≡C—Et 1524 5-F iPr C≡C-3-Pyridyl 1525 5-F iPr C≡C-2-furanyl 1526 5-F iPr C≡C-3-furanyl 1527 5-F iPr C≡C-2-thienyl 1528 5-F iPr C≡C-3-thienyl 1529 5-F Et C≡C-cycPr 1530 5-F Et C≡C-iPr 1531 5-F Et C≡C-nPr 1532 5-F Et C≡C—Et 1533 5-Cl cycPr C≡C-cycPr 1534 5-Cl cycPr C≡C-iPr 1535 5-Cl cycPr C≡C-nPr 1536 5-Cl cycPr C≡C—Et 1537 5-Cl cycPr C≡C-3-Pyridyl 1538 5-Cl cycPr C≡C-2-furanyl 1539 5-Cl cycPr C≡C-3-furanyl 1540 5-Cl cycPr C≡C-2-thienyl 1541 5-Cl cycPr C≡C-3-thienyl 1542 5-Cl iPr C≡C-cycPr 1543 5-Cl iPr C≡C-iPr 1544 5-Cl iPr C≡C-nPr 1545 5-Cl iPr C≡C—Et 1546 5-Cl iPr C≡C-3-Pyridyl 1547 5-Cl iPr C≡C-2-furanyl 1548 5-Cl iPr C≡C-3-furanyl 1549 5-Cl iPr C≡C-2-thienyl 1550 5-Cl iPr C≡C-3-thienyl 1551 5-Cl Et C≡C-cycPr 1552 5-Cl Et C≡C-iPr 1553 5-Cl Et C≡C-nPr 1554 5-Cl Et C≡C—Et 1555 6-OMe cycPr C≡C-cycPr 1556 6-OMe cycPr C≡C-iPr 1557 6-OMe cycPr C≡C-nPr 1558 6-OMe cycPr C≡C—Et 1559 6-OMe cycPr C≡C-3-Pyridyl 1560 6-OMe cycPr C≡C-2-furanyl 1561 6-OMe cycPr C≡C-3-furanyl 1562 6-OMe cycPr C≡C-2-thienyl 1563 6-OMe cycPr C≡C-3-thienyl 1564 6-OMe iPr C≡C-nPr 1565 6-OMe iPr C≡C—Et 1566 6-OMe iPr C≡C-3-Pyridyl 1567 6-OMe iPr C≡C-2-furanyl 1568 6-OMe iPr C≡C-3-furanyl 1569 6-OMe iPr C≡C-2-thienyl 1570 6-OMe iPr C≡C-3-thienyl 1571 6-OMe Et C≡C-cycPr 1572 6-OMe Et C≡C-iPr 1573 6-OMe Et C≡C-nPr 1574 6-OMe Et C≡C—Et 1575 5-F, 6-OMe cycPr C≡C-cycPr 1576 5-F, 6-OMe cycPr C≡C-iPr 1577 5-F, 6-OMe cycPr C≡C-nPr 1578 5-F, 6-OMe cycPr C≡C—Et 1579 5-F, 6-OMe cycPr C≡C-3-Pyridyl 1580 5-F, 6-OMe cycPr C≡C-2-furanyl 1581 5-F, 6-OMe cycPr C≡C-3-furanyl 1582 5-F, 6-OMe cycPr C≡C-2-thienyl 1583 5-F, 6-OMe cycPr C≡C-3-thienyl 1584 5-F, 6-OMe iPr C≡C-cycPr 1585 5-F, 6-OMe iPr C≡C-iPr 1586 5-F, 6-OMe iPr C≡C-nPr 1587 5-F, 6-OMe iPr C≡C—Et 1588 5-F, 6-OMe iPr C≡C-3-Pyridyl 1589 5-F, 6-OMe iPr C≡C-2-furanyl 1590 5-F, 6-OMe iPr C≡C-3-furanyl 1591 5-F, 6-OMe iPr C≡C-2-thienyl 1592 5-F, 6-OMe iPr C≡C-3-thienyl 1593 5-F, 6-OMe Et C≡C-cycPr 1594 5-F, 6-OMe Et C≡C-iPr 1595 5-F, 6-OMe Et C≡C-nPr 1596 5-F, 6-OMe Et C≡C—Et 1597 6-NMe₂ cycPr C≡C-cycPr 1598 6-NMe₂ cycPr C≡C-iPr 1599 6-NMe₂ cycPr C≡C-nPr 1600 6-NMe₂ cycPr C≡C—Et 1601 6-NMe₂ cycPr C≡C-3-Pyridyl 1602 6-NMe₂ cycPr C≡C-2-furanyl 1603 6-NMe₂ cycPr C≡C-3-furanyl 1604 6-NMe₂ cycPr C≡C-2-thienyl 1605 6-NMe₂ cycPr C≡C-3-thienyl 1606 6-NMe₂ iPr C≡C-cycPr 1607 6-NMe₂ iPr C≡C-iPr 1608 6-NMe₂ iPr C≡C-nPr 1609 6-NMe₂ iPr C≡C—Et 1610 6-NMe₂ iPr C≡C-3-Pyridyl 1611 6-NMe₂ iPr C≡C-2-furanyl 1612 6-NMe₂ iPr C≡C-3-furanyl 1613 6-NMe₂ iPr C≡C-2-thienyl 1614 6-NMe₂ iPr C≡C-3-thienyl 1615 6-NMe₂ Et C≡C-cycPr 1616 6-NMe₂ Et C≡C-iPr 1617 6-NMe₂ Et C≡C-nPr 1618 6-NMe₂ Et C≡C—Et 1619 6-COCH₃ cycPr C≡C-cycPr 1620 6-COCH₃ cycPr C≡C-iPr 1621 6-CCCH₃ cycPr C≡C-nPr 1622 6-COCH₃ cycPr C≡C—Et 1623 6-COCH₃ cycPr C≡C-3-Pyridyl 1624 6-COCH₃ cycPr C≡C-2-furanyl 1625 6-COCH₃ cycPr C≡C-3-furanyl 1626 6-COCH₃ cycPr C≡C-2-thienyl 1627 6-COCH₃ cycPr C≡C-3-thienyl 1628 6-COCH₃ iPr C≡C-cycPr 1629 6-COCH₃ iPr C≡C-iPr 1630 6-COCH₃ iPr C≡C-nPr 1631 6-COCH₃ iPr C≡C—Et 1632 6-COCH₃ iPr C≡C-3-Pyridyl 1633 6-COCH₃ iPr C≡C-2-furanyl 1634 6-COCH₃ iPr C≡C-3-furanyl 1635 6-COCH₃ iPr C≡C-2-thienyl 1636 6-COCH₃ iPr C≡C-3-thienyl 1637 6-COCH₃ Et C≡C-cycPr 1638 6-COCH₃ Et C≡C-iPr 1639 6-COCH₃ Et C≡C-nPr 1640 6-COCH₃ Et C≡C—Et 1641 6-CH₃ cycPr C≡C-cycPr 1642 6-CH₃ cycPr C≡C-nPr 1643 6-CH₃ cycPr C≡C—Et 1644 6-CH₃ cycPr C≡C-3-Pyridyl 1645 6-CH₃ cycPr C≡C-2-furanyl 1646 6-CH₃ cycPr C≡C-3-furanyl 1647 6-CH₃ cycPr C≡C-2-thienyl 1648 6-CH₃ cycPr C≡C-3-thienyl 1649 6-CH₃ iPr C≡C-nPr 1650 6-CH₃ iPr C≡C—Et 1651 6-CH₃ iPr C≡C-3-pyridyl 1652 6-CH₃ iPr C≡C-2-furanyl 1653 6-CH₃ iPr C≡C-3-furanyl 1654 6-CH₃ iPr C≡C-2-thienyl 1655 6-CH₃ iPr C≡C-3-thienyl 1656 6-CH₃ Et C≡C-cycPr 1657 6-CH₃ Et C≡C-nPr 1658 6,8-diCl cycPr C≡C-cycPr 1659 6,8-diCl cycPr C≡C-iPr 1660 6,8-diCl cycPr C≡C-nPr 1661 6,8-diCl cycPr C≡C—Et 1662 6,8-diCl cycPr C≡C-3-Pyridyl 1663 6,8-diCl cycPr C≡C-2-furanyl 1664 6,8-diCl cycPr C≡C-3-furanyl 1665 6,8-diCl cycPr C≡C-2-thienyl 1666 6,8-diCl cycPr C≡C-3-thienyl 1667 6,8-diCl iPr C≡C-cycPr 1668 6,8-diCl iPr C≡C-iPr 1669 6,8-diCl iPr C≡C-nPr 1670 6,8-diCl iPr C≡C—Et 1671 6,8-diCl iPr C≡C-3-Pyridyl 1672 6,8-diCl iPr C≡C-2-furanyl 1673 6,8-diCl iPr C≡C-3-furanyl 1674 6,8-diCl iPr C≡C-2-thienyl 1675 6,8-diCl iPr C≡C-3-thienyl 1676 6,8-diCl Et C≡C-cycPr 1677 6,8-diCl Et C≡C-iPr 1678 6,8-diCl Et C≡C-nPr 1679 6,8-diCl Et C≡C—Et 1680 5,6,8-triF cycPr C≡C-cycPr 1681 5,6,8-triF cycPr C≡C-iPr 1682 5,6,8-triF cycPr C≡C-nPr 1683 5,6,8-triF cycPr C≡C—Et 1684 5,6,8-triF cycPr C≡C-3-Pyridyl 1685 5,6,8-triF cycPr C≡C-2-furanyl 1686 5,6,8-triF cycPr C≡C-3-furanyl 1687 5,6,8-triF cycPr C≡C-2-thienyl 1688 5,6,8-triF cycPr C≡C-3-thienyl 1689 5,6,8-triF iPr C≡C-cycPr 1690 5,6,8-triF iPr C≡C-iPr 1691 5,6,8-triF iPr C≡C-nPr 1692 5,6,8-triF iPr C≡C—Et 1693 5,6,8-triF iPr C≡C-3-Pyridyl 1694 5,6,8-triF iPr C≡C-2-furanyl 1695 5,6,8-triF iPr C≡C-3-furanyl 1696 5,6,8-triF iPr C≡C-2-thienyl 1697 5,6,8-triF iPr C≡C-3-thienyl 1698 5,6,8-triF Et C≡C-cycPr 1699 5,6,8-triF Et C≡C-iPr 1700 5,6,8-triF Et C≡C-nPr 1701 5,6,8-triF Et C≡C—Et 1702 5,8-diF cycPr C≡C-cycPr 1703 5,8-diF cycPr C≡C-iPr 1704 5,8-diF cycPr C≡C-nPr 1705 5,8-diF cycPr C≡C—Et 1706 5,8-diF cycPr C≡C-3-Pyridyl 1707 5,8-diF cycPr C≡C-2-furanyl 1708 5,8-diF cycPr C≡C-3-furanyl 1709 5,8-diF cycPr C≡C-2-thienyl 1710 5,8-diF cycPr C≡C-3-thienyl 1711 5,8-diF iPr C≡C-cycPr 1712 5,8-diF iPr C≡C-iPr 1713 5,8-diF iPr C≡C-nPr 1714 5,8-diF iPr C≡C—Et 1715 5,8-diF iPr C≡C-3-Pyridyl 1716 5,8-diF iPr C≡C-2-furanyl 1717 5,8-diF iPr C≡C-3-furanyl 1718 5,8-diF iPr C≡C-2-thienyl 1719 5,8-diF iPr C≡C-3-thienyl 1720 5,8-diF Et C≡C-cycPr 1721 5,8-diF Et C≡C-iPr 1722 5,8-diF Et C≡C-nPr 1723 5,8-diF Et C≡C—Et 1724 6-iPr cycPr C≡C-cycPr 1725 6-iPr cycPr C≡C-iPr 1726 6-iPr cycPr C≡-nPr 1727 6-iPr cycPr C≡C—Et 1728 6-iPr cycPr C≡C-3-Pyridyl 1729 6-iPr cycPr C≡C-2-furanyl 1730 6-iPr cycPr C≡C-3-furanyl 1731 6-iPr cycPr C≡C-2-thienyl 1732 6-iPr cycPr C≡C-3-thienyl 1733 6-iPr iPr C≡C-cycPr 1734 6-iPr iPr C≡C-iPr 1735 6-iPr iPr C≡C-nPr 1736 6-iPr iPr C≡C—Et 1737 6-iPr iPr C≡C-3-Pyridyl 1738 6-iPr iPr C≡C-2-furanyl 1739 6-iPr iPr C≡C-3-furanyl 1740 6-iPr iPr C≡C-2-thienyl 1741 6-iPr iPr C≡C-3-thienyl 1742 6-iPr Et C≡C-cycPr 1743 6-iPr Et C≡C-iPr 1744 6-iPr Et C≡C-nPr 1745 6-iPr Et C≡C-Et 1746 6-OCF₃ cycPr C≡C-cycPr 1747 6-OCF₃ cycPr C≡C-nPr 1748 6-OCF₃ cycPr C≡C-iPr 1749 6-OCF₃ cycPr C≡C—Et 1750 6-OCF₃ cycPr C≡C-3-Pyridyl 1751 6-OCF₃ cycPr C≡C-2-furanyl 1752 6-OCF₃ cycPr C≡C-3-furanyl 1753 6-OCF₃ cycPr C≡C-2-thienyl 1754 6-OCF₃ cycPr C≡C-3-thienyl 1755 6-OCF₃ iPr C≡C-cycPr 1756 6-OCF₃ iPr C≡C-iPr 1757 6-OCF₃ iPr C≡C-nPr 1758 6-OCF₃ iPr C≡C—Et 1759 6-OCF₃ iPr C≡C-3-Pyridyl 1760 6-OCF₃ iPr C≡C-2-furanyl 1761 6-OCF₃ iPr C≡C-3-furanyl 1762 6-OCF₃ iPr C≡C-2-thienyl 1763 6-OCF₃ iPr C≡C-3-thienyl 1764 6-QCF₃ Et C≡C-cycPr 1765 6-OCF₃ Et C≡C-iPr 1766 6-OCF₃ Et C≡C-nPr 1767 6-OCF₃ Et C≡C—Et 1768 6-(pyrazol- cycPr C≡C-cycPr 5-yl) 1769 6-(pyrazol- cycPr C≡C-iPr 5-yl) 1770 6-(pyrazol- cycPr C≡C-nPr 5-yl) 1771 6-(pyrazol- cycPr C≡C—Et 5-yl) 1772 6-(pyrazol- cycPr C≡C-3-Pyridyl 5-yl) 1773 6-(pyrazol- cycPr C≡C-2-furanyl 5-yl) 1774 6-(pyrazol- cycPr C≡C-3-furanyl 5-yl) 1775 6-(pyrazol- cycPr C≡C-2-thienyl 5-yl) 1776 6-(pyrazol- cycPr C≡C-3-thienyl 5-yl) 1777 6-(pyrazol- iPr C≡C-cycPr 5-yl) 1778 6-(pyrazol- iPr C≡C-iPr 5-yl) 1779 6-(pyrazol- iPr C≡C-nPr 5-yl) 1780 6-(pyrazol- iPr C≡C—Et 5-yl) 1781 6-(pyrazol- iPr C≡C-3-Pyridyl 5-yl) 1782 6-(pyrazol- iPr C≡C-2-furanyl 5-yl) 1783 6-(pyrazol- iPr C≡C-3-furanyl 5-yl) 1784 6-(pyrazol- iPr C≡C-2-thienyl 5-yl) 1785 6-(pyrazol- iPr C≡C-3-thienyl 5-yl) 1786 6-(pyrazol- Et C≡C-cycPr 5-yl) 1787 6-(pyrazol- Et C≡C-iPr 5-yl) 1788 6-(pyrazol- Et C≡C-nPr 5-yl) 1789 6-(pyrazol- Et C≡C—Et 5-yl) 1790 H cycPr C≡C-cycPr 1791 H cycPr C≡C-iPr 1792 H cycPr C≡C-nPr 1793 H cycPr C≡C—Et 1794 H cycPr C≡C-3-Pyridyl 1795 H cycPr C≡C-2-furanyl 1796 H cycPr C≡C-3-furanyl 1797 H cycPr C≡C-2-thienyl 1798 H cycPr C≡C-3-thienyl 1799 H iPr C≡C-cycPr 1800 H iPr C≡C-iPr 1801 H iPr C≡C-nPr 1802 H iPr C≡C—Et 1803 H iPr C≡C-3-Pyridyl 1804 H iPr C≡C-2-furanyl 1805 H iPr C≡C-3-furanyl 1806 H iPr C≡C-2-thienyl 1807 H iPr C≡C-3-thienyl 1808 H Et C≡C-cycPr 1809 H Et C≡C-iPr 1810 H Et C≡C-nPr 1811 H Et C≡C—Et 1812 6-Ph cycPr C≡C-cycPr 1813 6-Ph cycPr C≡C-iPr 1814 6-Ph cycPr C≡C-nPr 1815 6-Ph cycPr C≡C—Et 1816 6-Ph cycPr C≡C-3-Pyridyl 1817 6-Ph cycPr C≡C-2-furanyl 1818 6-Ph cycPr C≡C-3-furanyl 1819 6-Ph cycPr C≡C-2-thienyl 1820 6-Ph cycPr C≡C-3-thienyl 1821 6-Ph iPr C≡C-cycPr 1822 6-Ph iPr C≡C-iPr 1823 6-Ph iPr C≡C-nPr 1824 6-Ph iPr C≡C—Et 1825 6-Ph iPr C≡C-3-Pyridyl 1826 6-Ph iPr C≡C-2-furanyl 1827 6-Ph iPr C≡C-3-furanyl 1828 6-Ph iPr C≡C-2-thienyl 1829 6-Ph iPr C≡C-3-thienyl 1830 6-Ph Et C≡C-cycPr 1831 6-Ph Et C≡C-iPr 1832 6-Ph Et C≡C-nPr 1833 6-Ph Et C≡C—Et 1834 6-CN cycPr C≡C-cycPr 1835 6-CN cycPr C≡C-iPr 1836 6-CN cycPr C≡C-nPr 1837 6-CN cycPr C≡C—Et 1838 6-CN cycPr C≡C-3-Pyridyl 1839 6-CN cycPr C≡C-2-furanyl 1840 6-CN cycPr C≡C-3-furanyl 1841 6-CN cycPr C≡C-2-thienyl 1842 6-CN cycPr C≡C-3-thienyl 1843 6-CN iPr C≡C-cycPr 1844 6-CN iPr C≡C-iPr 1845 6-CN iPr C≡C-nPr 1846 6-CN iPr C≡C—Et 1847 6-CN iPr C≡C-3-Pyridyl 1848 6-CN iPr C≡C-2-furanyl 1849 6-CN iPr C≡C-3-furanyl 1850 6-CN iPr C≡C-2-thienyl 1851 6-CN iPr C≡C-3-thienyl 1852 6-CN Et C≡C-cycPr 1853 6-CN Et C≡C-iPr 1854 6-CN Et C≡C-nPr 1855 6-CN Et C≡C—Et 1856 6-NO₂ cycPr C≡C-cycPr 1857 6-NO₂ cycPr C≡C-iPr 1858 6-NO₂ cycPr C≡C-nPr 1859 6-NO₂ cycPr C≡C—Et 1860 6-NO₂ cycPr C≡C-3-Pyridyl 1861 6-NO₂ cycPr C≡C-2-furanyl 1862 6-NO₂ cycPr C≡C-3-furanyl 1863 6-NO₂ cycPr C≡C-2-thienyl 1864 6-NO₂ cycPr C≡C-3-thienyl 1865 6-NO₂ iPr C≡C-cycPr 1866 6-NO₂ iPr C≡C-iPr 1867 6-NO₂ iPr C≡C-nPr 1868 6-NO₂ iPr C≡C—Et 1869 6-NO₂ iPr C≡C-3-Pyridyl 1870 6-NO₂ iPr C≡C-2-furanyl 1871 6-NO₂ iPr C≡C-3-furanyl 1872 6-NO₂ iPr C≡C-2-thienyl 1873 6-NO₂ iPr C≡C-3-thienyl 1874 6-NO₂ Et C≡C-cycPr 1875 6-NO₂ Et C≡C-iPr 1876 6-NO₂ Et C≡C-nPr 1877 6-NO₂ Et C≡C—Et 1878 6-NHMe cycPr C≡C-cycPr 1879 6-NHMe cycPr C≡C-iPr 1880 6-NHMe cycPr C≡C-nPr 1881 6-NHMe cycPr C≡C—Et 1882 6-NHMe cycPr C≡C-3-Pyridyl 1883 6-NHMe cycPr C≡C-2-furanyl 1884 6-NHMe cycPr C≡C-3-furanyl 1885 6-NHMe cycPr C≡C-2-thlenyl 1886 6-NHMe cycPr C≡C-3-thienyl 1887 6-NHMe iPr C≡C-cycPr 1888 6-NHMe iPr C≡C-iPr 1889 6-NHMe iPr C≡C-nPr 1890 6-NHMe iPr C≡C—Et 1891 6-NHMe iPr C≡C-3-Pyridyl 1892 6-NHMe iPr C≡C-2-furanyl 1893 6-NHMe iPr C≡C-3-furanyl 1894 6-NHMe iPr C≡C-2-thienyl 1895 6-NHMe iPr C≡C-3-thienyl 1896 6-NHMe Et C≡C-cycPr 1897 6-NHMe Et C≡C-iPr 1898 6-NHMe Et C≡C-nPr 1899 6-NHMe Et C≡C—Et 1900 6,7-diCl cycPr C≡C-cycPr 1901 6,7-diCl cycPr C≡C-nPr 1902 6,7-diCl cycPr C≡C—Et 1993 6,7-diCl cycPr C≡C-3-Pyridyl 1904 6,7-diCl cycPr C≡C-2-furanyl 1905 6,7-diCl cycPr C≡C-3-furanyl 1906 6,7-diCl cycPr C≡C-2-thienyl 1907 6,7-diCl cycPr C≡C-3-thienyl 1908 6,7-diCl iPr C≡C-cycPr 1909 6,7-diCl iPr C≡C-nPr 1910 6,7-diCl iPr C≡C—Et 1911 6,7-diCl iPr C≡C-3-Pyridyl 1912 6,7-diCl iPr C≡C-2-furanyl 1913 6,7-diCl iPr C≡C-3-furanyl 1914 6,7-diCl iPr C≡C-2-thienyl 1915 6,7-diCl iPr C≡C-3-thienyl 1916 6,7-diCl Et C≡C-cycPr 1917 6,7-diCl Et C≡C-iPr 1918 6,7-diCl Et C≡C-nPr 1919 6,7-diCl Et C≡C—Et 1920 7-Cl cycPr C≡C-nPr 1921 7-Cl cycPr C≡C—Et 1922 7-Cl cycPr C≡C-3-Pyridyl 1923 7-Cl cycPr C≡C-2-furanyl 1924 7-Cl cycPr C≡C-3-furanyl 1925 7-Cl cycPr C≡C-2-thienyl 1926 7-Cl cycPr C≡C-3-thienyl 1927 7-Cl iPr C≡C-nPr 1928 7-Cl iPr C≡C—Et 1929 7-Cl iPr C≡C-3-Pyridyl 1930 7-Cl iPr C≡C-2-furanyl 1931 7-CI iPr C≡C-3-furanyl 1932 7-Cl iPr C≡C-2-thienyl 1933 7-Cl iPr C≡C-3-thienyl 1934 7-Cl Et C≡C-cycPr 1935 7-Cl Et C≡C-iPr 1936 7-Cl Et C≡C-nPr 1937 7-Cl Et C≡C—Et *Unless otherwise noted, stereochemistry is (+/−).

TABLE 4

Ex. # W X Y Z R¹ R² 2001 CH CCl CH N CF₃ C≡C—nPr 2002 CH CCl CH N CF₃ C≡C—Bu 2003 CH CCl CH N CF₃ C≡C—iBu 2004 CH CCl CH N CF₃ C≡C—tBu 2005 CH CCl CH N CF₃ C≡C—Et 2006 CH CCl CH N CF₃ C≡C—Me 2007 CH CCl CH N CF₃ C≡C—Ph 2008 CH CCl CH N CF₃ C≡C-2-Pyridyl 2009 CH CCl CH N CF₃ C≡C-3-Pyridyl 2010 CH CCl CH N CF₃ C≡C-4-Pyridyl 2011 CH CCl CH N CF₃ C≡C-2-furanyl 2012 CH CCl CH N CF₃ C≡C-3-furanyl 2013 CH CCl CH N CF₃ C≡C-2-thienyl 2014 CH CCl CH N CF₃ C≡C-3-thienyl 2015 CH CCl CH N CF₃ CH═CH—cycPr 2016 CH CCl CH N CF₃ CH═CH—iPr 2017 CH CCl CH N CF₃ CH═CH—nPr 2018 CH CCl CH N CF₃ CH═CH—Bu 2019 CH CCl CH N CF₃ CH═CH—iBu 2020 CH CCl CH N CF₃ CH═CH—tBu 2021 CH CCl CH N CF₃ CH═CH—Et 2022 CH CCl CH N CF₃ CH═CH—Me 2023 CH CCl CH N CF₃ CH═CH—Ph 2024 CH CCl CH N CF₃ CH═CH-2-Pyridyl 2025 CH CCl CH N CF₃ CH═CH-3-Pyridyl 2026 CH CCl CH N CF₃ CH═CH-4-Pyridyl 2027 CH CCl CH N CF₃ CH═CH-2-furanyl 2028 CH CCl CH N CF₃ CH═CH-3-furanyl 2029 CH CCl CH N CF₃ CH═CH-2-thienyl 2030 CH CCl CH N CF₃ CH═CH-3-thienyl 2031 CH CCl CH N CF₃ CH₂CH₂CH₂CH₂CH₃ 2032 CH CCl CH N CF₃ CH₂CH₂CH(CH₃)₂ 2033 CH CCl CH N CF₃ CH₂CH₂CH₂CH₃ 2034 CH CCl CH N CF₃ CH₂CH₂CH₃ 2035 CH CCl CH N CF₃ CH₂CH₂—cycPr 2036 CH CCl CH N CF₃ CH₂CH₂—tBu 2037 CH CCl CH N CF₃ CH₂CH₂-2-Pyridyl 2038 CH CCl CH N CF₃ CH₂CH₂-3-Pyridyl 2039 CH CCl CH N CF₃ CH₂CH₂-4-Pyridyl 2040 CH CCl CH N CF₃ CH₂CH₂-2-furanyl 2041 CH CCl CH N CF₃ CH₂CH₂-3-furanyl 2042 CH CCl CH N CF₃ CH₂CH₂-2-thienyl 2043 CH CCl CH N CF₃ CH₂CH₂-3-thienyl 2044 CH C(OCH₃) CH N CF₃ C≡C—cycPr 2045 CH C(OCH₃) CH N CF₃ C≡C—iPr 2046 CH C(OCH₃) CH N CF₃ C≡C—nPr 2047 CH C(OCH₃) CH N CF₃ C≡C—Bu 2048 CH C(OCH₃) CH N CF₃ C≡C—iBu 2049 CH C(OCH₃) CH N CF₃ C≡C—tBu 2050 CH C(OCH₃) CH N CF₃ C≡C—Et 2051 CH C(OCH₃) CH N CF₃ C≡C—Me 2052 CH C(OCH₃) CH N CF₃ C≡C—Ph 2053 CH C(OCH₃) CH N CF₃ C≡C-2-Pyridyl 2054 CH C(OCH₃) CH N CF₃ C≡C-3-Pyridyl 2055 CH C(OCH₃) CH N CF₃ C≡C-4-Pyridyl 2056 CH C(OCH₃) CH N CF₃ C≡C-2-furanyl 2057 CH C(OCH₃) CH N CF₃ C≡C-3-furanyl 2058 CH C(OCH₃) CH N CF₃ C≡C-2-thienyl 2059 CH C(OCH₃) CH N CF₃ C≡C-3-thienyl 2060 CH C(OCH₃) CH N CF₃ CH═CH—cycPr 2061 CH C(OCH₃) CH N CF₃ CH═CH—iPr 2062 CH C(OCH₃) CH N CF₃ CH═CH—nPr 2063 CH C(OCH₃) CH N CF₃ CH═CH—Bu 2064 CH C(OCH₃) CH N CF₃ CH═CH—iBu 2065 CH C(OCH₃) CH N CF₃ CH═CH—tBu 2066 CH C(OCH₃) CH N CF₃ CH═CH—Et 2067 CH C(OCH₃) CH N CF₃ CH═CH—Me 2068 CH C(OCH₃) CH N CF₃ CH═CH—Ph 2069 CH C(OCH₃) CH N CF₃ CH═CH-2-Pyridyl 2070 CH C(OCH₃) CH N CF₃ CH═CH-3-Pyridyl 2071 CH C(OCH₃) CH N CF₃ CH═CH-4-Pyridyl 2072 CH C(OCH₃) CH N CF₃ CH═CH-2-furanyl 2073 CH C(OCH₃) CH N CF₃ CH═CH-3-furanyl 2074 CH C(OCH₃) CH N CF₃ CH═CH-2-thienyl 2075 CH C(OCH₃) CH N CF₃ CH═CH-3-thienyl 2076 CH C(OCH₃) CH N CF₃ CH₂CH₂CH₂CH₂CH₃ 2077 CH C(OCH₃) CH N CF₃ CH₂CH₂CH(CH₃)₂ 2078 CH C(OCH₃) CH N CF₃ CH₂CH₂CH₂CH₃ 2079 CH C(OCH₃) CH N CF₃ CH₂CH₂CH₃ 2080 CH C(OCH₃) CH N CF₃ CH₂CH₂—cycPr 2081 CH C(OCH₃) CH N CF₃ CH₂CH₂—tBu 2082 CH C(OCH₃) CH N CF₃ CH₂CH₂—Ph 2083 CH C(OCH₃) CH N CF₃ CH₂CH₂-2-Pyridyl 2084 CH C(OCH₃) CH N CF₃ CH₂CH₂-3-Pyridyl 2085 CH C(OCH₃) CH N CF₃ CH₂CH₂-4-Pyridyl 2086 CH C(OCH₃) CH N CF₃ CH₂CH₂-2-furanyl 2087 CH C(OCH₃) CH N CF₃ CH₂CH₂-3-furanyl 2088 CH C(OCH₃) CH N CF₃ CH₂CH₂-2-thienyl 2089 CH C(OCH₃) CH N CF₃ CH₂CH₂-3-thienyl 2090 CH CH CH N CF₃ C≡C—cycPr 2091 CH CH CH N CF₃ C≡C—iPr 2092 CH CH CH N CF₃ C≡C—nPr 2093 CH CH CH N CF₃ C≡C—Et 2094 CH CH CH N CF₃ C≡C-3-Pyridyl 2095 CH CH CH N CF₃ C≡C-2-furanyl 2096 CH CH CH N CF₃ C≡C-3-furanyl 2097 CH CH CH N CF₃ C≡C-2-thienyl 2098 CH CH CH N CF₃ C≡C-3-thienyl 2099 CH CCl N CH CF₃ C≡C—iPr 2100 CH CCl N CH CF₃ C≡C—nPr 2101 CH CCl N CH CF₃ C≡C—Bu 2102 CH CCl N CH CF₃ C≡C—iBu 2103 CH CCl N CH CF₃ C≡C—tBu 2104 CH CCl N CH CF₃ C≡C—Et 2105 CH CCl N CH CF₃ C≡C—Me 2106 CH CCl N CH CF₃ C≡C—Ph 2107 CH CCl N CH CF₃ C≡C-2-Pyridyl 2108 CH CCl N CH CF₃ C≡C-3-Pyridyl 2109 CH CCl N CH CF₃ C≡C-4-Pyridyl 2110 CH CCl N CH CF₃ C≡C-2-furanyl 2111 CH CCl N CH CF₃ C≡C-3-furanyl 2112 CH CCl N CH CF₃ C≡C-2-thienyl 2113 CH CCl N CH CF₃ C≡C-3-thienyl 2114 CH CCl N CH CF₃ CH═CH—cycPr 2115 CH CCl N CH CF₃ CH═CH—iPr 2116 CH CCl N CH CF₃ CH═CH—nPr 2117 CH CCl N CH CF₃ CH═CH—Bu 2118 CH CCl N CH CF₃ CH═CH—iBu 2119 CH CCl N CH CF₃ CH═CH—tBu 2120 CH CCl N CH CF₃ CH═CH—Et 2121 CH CCl N CH CF₃ CH═CH—Me 2122 CH CCl N CH CF₃ CH═CH—Ph 2123 CH CCl N CH CF₃ CH═CH-2-Pyridyl 2124 CH CCl N CH CF₃ CH═CH-3-Pyridyl 2125 CH CCl N CH CF₃ CH═CH-4-Pyridyl 2126 CH CCl N CH CF₃ CH═CH-2-furanyl 2127 CH CCl N CH CF₃ CH═CH-3-furanyl 2128 CH CCl N CH CF₃ CH═CH-2-thienyl 2129 CH CCl N CH CF₃ CH═CH-3-thienyl 2130 CH CCl N CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2131 CH CCl N CH CF₃ CH₂CH₂CH(CH₃)₂ 2132 CH CCl N CH CF₃ CH₂CH₂CH₂CH₃ 2133 CH CCl N CH CF₃ CH₂CH₂CH₃ 2134 CH CCl N CH CF₃ CH₂CH₂—cycPr 2135 CH CCl N CH CF₃ CH₂CH₂—tBu 2136 CH CCl N CH CF₃ CH₂CH₂—Ph 2137 CH CCl N CH CF₃ CH₂CH₂-2-Pyridyl 2138 CH CCl N CH CF₃ CH₂CH₂-3-Pyridyl 2139 CH CCl N CH CF₃ CH₂CH₂-4-Pyridyl 2140 CH CCl N CH CF₃ CH₂CH₂-2-furanyl 2141 CH CCl N CH CF₃ CH₂CH₂-3-furanyl 2142 CH CCl N CH CF₃ CH₂CH₂-2-thienyl 2143 CH CCl N CH CF₃ CH₂CH₂-3-thienyl 2144 CH C(OCH₃) N CH CF₃ C≡C—iPr 2145 CH C(OCH₃) N CH CF₃ C≡C—nPr 2146 CH C(OCH₃) N CH CF₃ C≡C—Bu 2147 CH C(OCH₃) N CH CF₃ C≡C—iBu 2148 CH C(OCH₃) N CH CF₃ C≡C—tBu 2149 CH C(OCH₃) N CH CF₃ C≡C—Et 2150 CH C(OCH₃) N CH CF₃ C≡C—Me 2151 CH C(OCH₃) N CH CF₃ C≡C—Ph 2152 CH C(OCH₃) N CH CF₃ C≡C-2-Pyridyl 2153 CH C(OCH₃) N CH CF₃ C≡C-3-Pyridyl 2154 CH C(OCH₃) N CH CF₃ C≡C-4-Pyridyl 2155 CH C(OCH₃) N CH CF₃ C≡C-2-furanyl 2156 CH C(OCH₃) N CH CF₃ C≡C-3-furanyl 2157 CH C(OCH₃) N CH CF₃ C≡C-2-thienyl 2158 CH C(OCH₃) N CH CF₃ C≡C-3-thienyl 2159 CH C(OCH₃) N CH CF₃ CH═CH—cycPr 2160 CH C(OCH₃) N CH CF₃ CH═CH—iPr 2161 CH C(OCH₃) N CH CF₃ CH═CH—nPr 2162 CH C(OCH₃) N CH CF₃ CH═CH—Bu 2163 CH C(OCH₃) N CH CF₃ CH═CH—iBu 2164 CH C(OCH₃) N CH CF₃ CH═CH—tBu 2165 CH C(OCH₃) N CH CF₃ CH═CH—Et 2166 CH C(OCH₃) N CH CF₃ CH═CH—Me 2167 CH C(OCH₃) N CH CF₃ CH═CH—Ph 2168 CH C(OCH₃) N CH CF₃ CH═CH-2-Pyridyl 2169 CH C(OCH₃) N CH CF₃ CH═CH-3-Pyridyl 2170 CH C(OCH₃) N CH CF₃ CH═CH-4-Pyridyl 2171 CH C(OCH₃) N CH CF₃ CH═CH-2-furanyl 2172 CH C(OCH₃) N CH CF₃ CH═CH-3-furanyl 2173 CH C(OCH₃) N CH CF₃ CH═CH-2-thienyl 2174 CH C(OCH₃) N CH CF₃ CH═CH-3-thienyl 2175 CH C(OCH₃) N CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2176 CH C(OCH₃) N CH CF₃ CH₂CH₂CH(CH₃)₂ 2177 CH C(OCH₃) N CH CF₃ CH₂CH₂CH₂CH₃ 2178 CH C(OCH₃) N CH CF₃ CH₂CH₂CH₃ 2179 CH C(OCH₃) N CH CF₃ CH₂CH₂—cycPr 2180 CH C(OCH₃) N CH CF₃ CH₂CH₂—tBu 2181 CH C(OCH₃) N CH CF₃ CH₂CH₂—Ph 2182 CH C(OCH₃) N CH CF₃ CH₂CH₂-2-Pyridyl 2183 CH C(OCH₃) N CH CF₃ CH₂CH₂-3-Pyridyl 2184 CH C(OCH₃) N CH CF₃ CH₂CH₂-4-Pyridyl 2185 CH C(OCH₃) N CH CF₃ CH₂CH₂-2-furanyl 2186 CH C(OCH₃) N CH CF₃ CH₂CH₂-3-furanyl 2187 CH C(OCH₃) N CH CF₃ CH₂CH₂-2-thienyl 2188 CH C(OCH₃) N CH CF₃ CH₂CH₂-3-thienyl 2189 CH CH N CH CF₃ C≡C—cycPr 2190 CH CH N CH CF₃ C≡C—iPr 2191 CH CH N CH CF₃ C≡C—nPr 2192 CH CH N CH CF₃ C≡C—Et 2193 CH CH N CH CF₃ C≡C-3-Pyridyl 2194 CH CH N CH CF₃ C≡C-2-furanyl 2195 CH CH N CH CF₃ C≡C-3-furanyl 2196 CH CH N CH CF₃ C≡C-2-thienyl 2197 CH CH N CH CF₃ C≡C-3-thienyl 2198 CCl N CH CH CF₃ C≡C—cycPr 2199 CCl N CH CH CF₃ C≡C—iPr 2200 CCl N CH CH CF₃ C≡C—nPr 2201 CCl N CH CH CF₃ C≡C—Bu 2202 CCl N CH CH CF₃ C≡C—iBu 2203 CCl N CH CH CF₃ C≡C—tBu 2204 CCl N CH CH CF₃ C≡C—Et 2205 CCl N CH CH CF₃ C≡C—Me 2206 CCl N CH CH CF₃ C≡C—Ph 2207 CCl N CH CH CF₃ C≡C-2-Pyridyl 2208 CCl N CH CH CF₃ C≡C-3-Pyridyl 2209 CCl N CH CH CF₃ C≡C-4-Pyridyl 2210 CCl N CH CH CF₃ C≡C-2-furanyl 2211 CCl N CH CH CF₃ C≡C-3-furanyl 2212 CCl N CH CH CF₃ C≡C-2-thienyl 2213 CCl N CH CH CF₃ C≡C-3-thienyl 2214 CCl N CH CH CF₃ CH═CH—cycPr 2215 CCl N CH CH CF₃ CH═CH—iPr 2216 CCl N CH CH CF₃ CH═CH—nPr 2217 CCl N CH CH CF₃ CH═CH—Bu 2218 CCl N CH CH CF₃ CH═CH—iBu 2219 CCl N CH CH CF₃ CH═CH—tBu 2220 CCl N CH CH CF₃ CH═CH—Et 2221 CCl N CH CH CF₃ CH═CH—Me 2222 CCl N CH CH CF₃ CH═CH—Ph 2223 CCl N CH CH CF₃ CH═CH-2-Pyridyl 2224 CCl N CH CH CF₃ CH═CH-3-Pyridyl 2225 CCl N CH CH CF₃ CH═CH-4-Pyridyl 2226 CCl N CH CH CF₃ CH═CH-2-furanyl 2227 CCl N CH CH CF₃ CH═CH-3-furanyl 2228 CCl N CH CH CF₃ CH═CH-2-thienyl 2229 CCl N CH CH CF₃ CH═CH-3-thienyl 2230 CCl N CH CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2231 CCl N CH CH CF₃ CH₂CH₂CH(CH₃)₂ 2232 CCl N CH CH CF₃ CH₂CH₂CH₂CH₃ 2233 CCl N CH CH CF₃ CH₂CH₂CH₃ 2234 CCl N CH CH CF₃ CH₂CH₂—cycPr 2235 CCl N CH CH CF₃ CH₂CH₂—tBu 2236 CCl N CH CH CF₃ CH₂CH₂—Ph 2237 CCl N CH CH CF₃ CH₂CH₂-2-Pyridyl 2238 CCl N CH CH CF₃ CH₂CH₂-3-Pyridyl 2239 CCl N CH CH CF₃ CH₂CH₂-4-Pyridyl 2240 CCl N CH CH CF₃ CH₂CH₂-2-furanyl 2241 CCl N CH CH CF₃ CH₂CH₂-3-furanyl 2242 CCl N CH CH CF₃ CH₂CH₂-2-thienyl 2243 CCl N CH CH CF₃ CH₂CH₂-3-thienyl 2244 CH N CH CH CF₃ C≡C—iPr 2245 CH N CH CH CF₃ C≡C—nPr 2246 CH N CH CH CF₃ C≡C—Et 2247 CH N CH CH CF₃ C≡C-3-Pyridyl 2248 CH N CH CH CF₃ C≡C-2-furanyl 2249 CH N CH CH CF₃ C≡C-3-furanyl 2250 CH N CH CH CF₃ C≡C-2-thienyl 2251 CH N CH CH CF₃ C≡C-3-thienyl 2252 N CCl CH CH CF₃ C≡C—cycPr 2253 N CCl CH CH CF₃ C≡C—iPr 2254 N CCl CH CH CF₃ C≡C—nPr 2255 N CCl CH CH CF₃ C≡C—Bu 2256 N CCl CH CH CF₃ C≡C—iBu 2257 N CCl CH CH CF₃ C≡C—tBu 2258 N CCl CH CH CF₃ C≡C—Et 2259 N CCl CH CH CF₃ C≡C—Me 2260 N CCl CH CH CF₃ C≡C—Ph 2261 N CCl CH CH CF₃ C≡C-2-Pyridyl 2262 N CCl CH CH CF₃ C≡C-3-Pyridyl 2263 N CCl CH CH CF₃ C≡C-4-Pyridyl 2264 N CCl CH CH CF₃ C≡C-2-furanyl 2265 N CCl CH CH CF₃ C≡C-3-furanyl 2266 N CCl CH CH CF₃ C≡C-2-thienyl 2267 N CCl CH CH CF₃ C≡C-3-thienyl 2268 N CCl CH CH CF₃ CH═CH—cycPr 2269 N CCl CH CH CF₃ CH═CH—iPr 2270 N CCl CH CH CF₃ CH═CH—nPr 2271 N CCl CH CH CF₃ CH═CH—Bu 2272 N CCl CH CH CF₃ CH═CH—iBu 2273 N CCl CH CH CF₃ CH═CH—tBu 2274 N CCl CH CH CF₃ CH═CH—Et 2275 N CCl CH CH CF₃ CH═CH—Me 2276 N CCl CH CH CF₃ CH═CH—Ph 2277 N CCl CH CH CF₃ CH═CH-2-Pyridyl 2278 N CCl CH CH CF₃ CH═CH-3-Pyridyl 2279 N CCl CH CH CF₃ CH═CH-4-Pyridyl 2280 N CCl CH CH CF₃ CH═CH-2-furanyl 2281 N CCl CH CH CF₃ CH═CH-3-furanyl 2282 N CCl CH CH CF₃ CH═CH-2-thienyl 2283 N CCl CH CH CF₃ CH═CH-3-thienyl 2284 N CCl CH CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2285 N CCl CH CH CF₃ CH₂CH₂CH(CH₃)₂ 2286 N CCl CH CH CF₃ CH₂CH₂CH₂CH₃ 2287 N CCl CH CH CF₃ CH₂CH₂CH₃ 2288 N CCl CH CH CF₃ CH₂CH₂—cycPr 2289 N CCl CH CH CF₃ CH₂CH₂—tBu 2290 N CCl CH CH CF₃ CH₂CH₂—Ph 2291 N CCl CH CH CF₃ CH₂CH₂-2-Pyridyl 2292 N CCl CH CH CF₃ CH₂CH₂-3-Pyridyl 2293 N CCl CH CH CF₃ CH₂CH₂-4-Pyridyl 2294 N CCl CH CH CF₃ CH₂CH₂-2-furanyl 2295 N CCl CH CH CF₃ CH₂CH₂-3-furanyl 2296 N CCl CH CH CF₃ CH₂CH₂-2-thienyl 2297 N CCl CH CH CF₃ CH₂CH₂-3-thienyl 2298 N C(OCH₃) CH CH CF₃ C≡C—cycPr 2299 N C(OCH₃) CH CH CF₃ C≡C—iPr 2300 N C(OCH₃) CH CH CF₃ C≡C—nPr 2301 N C(OCH₃) CH CH CF₃ C≡C—Bu 2302 N C(OCH₃) CH CH CF₃ C≡C—iBu 2303 N C(OCH₃) CH CH CF₃ C≡C—tBu 2304 N C(OCH₃) CH CH CF₃ C≡C—Et 2305 N C(OCH₃) CH CH CF₃ C≡C—Me 2306 N C(OCH₃) CH CH CF₃ C≡C—Ph 2307 N C(OCH₃) CH CH CF₃ C≡C-2-Pyridyl 2308 N C(OCH₃) CH CH CF₃ C≡C-3-Pyridyl 2309 N C(OCH₃) CH CH CF₃ C≡C-4-Pyridyl 2310 N C(OCH₃) CH CH CF₃ C≡C-2-furanyl 2311 N C(OCH₃) CH CH CF₃ C≡C-3-furanyl 2312 N C(OCH₃) CH CH CF₃ C≡C-2-thienyl 2313 N C(OCH₃) CH CH CF₃ C≡C-3-thienyl 2314 N C(OCH₃) CH CH CF₃ CH═CH—cycPr 2315 N C(OCH₃) CH CH CF₃ CH═CH—iPr 2316 N C(OCH₃) CH CH CF₃ CH═CH—nPr 2317 N C(OCH₃) CH CH CF₃ CH═CH—Bu 2318 N C(OCH₃) CH CH CF₃ CH═CH—iBu 2319 N C(OCH₃) CH CH CF₃ CH═CH—tBu 2320 N C(OCH₃) CH CH CF₃ CH═CH—Et 2321 N C(OCH₃) CH CH CF₃ CH═CH—Me 2322 N C(OCH₃) CH CH CF₃ CH═CH—Ph 2323 N C(OCH₃) CH CH CF₃ CH═CH-2-Pyridyl 2324 N C(OCH₃) CH CH CF₃ CH═CH-3-Pyridyl 2325 N C(OCH₃) CH CH CF₃ CH═CH-4-Pyridyl 2326 N C(OCH₃) CH CH CF₃ CH═CH-2-furanyl 2327 N C(OCH₃) CH CH CF₃ CH═CH-3-furanyl 2328 N C(OCH₃) CH CH CF₃ CH═CH-2-thienyl 2329 N C(OCH₃) CH CH CF₃ CH═CH-3-thienyl 2330 N C(OCH₃) CH CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2331 N C(OCH₃) CH CH CF₃ CH₂CH₂CH(CH₃)₂ 2332 N C(OCH₃) CH CH CF₃ CH₂CH₂CH₂CH₃ 2333 N C(OCH₃) CH CH CF₃ CH₂CH₂CH₃ 2334 N C(OCH₃) CH CH CF₃ CH₂CH₂—cycPr 2335 N C(OCH₃) CH CH CF₃ CH₂CH₂—tBu 2336 N C(OCH₃) CH CH CF₃ CH₂CH₂—Ph 2337 N C(OCH₃) CH CH CF₃ CH₂CH₂-2-Pyridyl 2338 N C(OCH₃) CH CH CF₃ CH₂CH₂-3-Pyridyl 2339 N C(OCH₃) CH CH CF₃ CH₂CH₂-4-Pyridyl 2340 N C(OCH₃) CH CH CF₃ CH₂CH₂-2-furanyl 2341 N C(OCH₃) CH CH CF₃ CH₂CH₂-3-furanyl 2342 N C(OCH₃) CH CH CF₃ CH₂CH₂-2-thienyl 2343 N C(OCH₃) CH CH CF₃ CH₂CH₂-3-thienyl 2344 N CH CH CH CF₃ C≡C—cycPr 2345 N CH CH CH CF₃ C≡C—iPr 2346 N CH CH CH CF₃ C≡C—nPr 2347 N CH CH CH CF₃ C≡C—Et 2348 N CH CH CH CF₃ C≡C-3-Pyridyl 2349 N CH CH CH CF₃ C≡C-2-furanyl 2350 N CH CH CH CF₃ C≡C-3-furanyl 2351 N CH CH CH CF₃ C≡C-2-thienyl 2352 N CH CH CH CF₃ C≡C-3-thienyl *Unless otherwise noted, stereochemistry is (+/−).

TABLE 5

Ex. # G R¹ R² m.p. (° C.) Mass Spec 2401 6-Cl cycPr C≡C—Et   137-138.5 2402 6-Cl CF₃ C≡C—Et 178 2403 6-Cl Et C≡C—Et 175-176 2404 6-Cl CH₃ CH₃ 202 212.0440 2405 6-Cl CH₃ C≡C—cycPr 184 2406 6-Cl CH₃ CH₃ 221-222 228.0262 2407 6-Cl CH₃ C≡C—iPr 168 264.0790 2408 6-Cl CF₃ CH═CH—cycPr(cis) 2409 6-Cl CF₃ C≡C—iPr 167-168 2410 6-Cl CF₃ CH═CH—iPr(cis) 146-147 2411 6-Cl CF₃ CH₂CH₂—iPr 129-131 2412 6-Cl CF₃ C≡C—iPr 116-118 2413 6-Cl CF₃ CH═CH—iPr(trans) 127-129 2414 6-Cl OMe CH₂CH₂—Ph 318.0897 2415 6-Cl OEt Ph 304 (MH⁺) 2416 6-Cl CF₃ C≡C-1-d-cycPr 180-181 317.0406 2417 6-Cl CF₃ C≡C-1-d-cycPr 133-134 317.0417 2418 6-Cl CF₃ C≡C-1-Me—cycPr 158-159 347.0785 2419 6-Cl CF₃ Butyl 135-136 2420 6-Cl CF₃ C≡C—cycBu 183-185 330.0495 2421 6-Cl CF₃ C(Me)₂CC≡CCH 2422 6-Cl CF₃ CF₃ 148-149 2423 6-Cl CF₃ C≡C—CF₃ 155-156 2424 6-Cl CF₃ Pentyl 2425 6-Cl CF₃ C≡C—Ph 352.0353 2426 6-Cl CF₃ C≡C-3-py 2427 6-Cl CF₃ C≡C-2-thiazole 2428 6-Cl CF₃ NH—iBu 182-183 2429 6-Cl CF₃ C≡C-4-py 2430 6-Cl CH₃ C≡C—Ph 181-182 298.0620 2431 6-Cl iPr C≡C—iPr oil 292.1106 2432 6-Cl iPr C≡C—iBu oil 306.1268 2433 6-Cl iPr C≡C—cycPr amorphous 290.0938 2434 6-Cl iPr C≡C—Ph 177-178 326.0955 2435 6-Cl Et C≡C—cycPr 183-184 276.0792 2436 6-Cl Et C≡C—iPr 143-144 278.0958 2437 6-Cl Et C≡C—Ph 165-166 312.0790 2438 6-Cl Et C≡C—iBu 136-137 292.1100 2439 6-Cl cycPr C≡C—cycPr 142-143 288.0789 2440 6-Cl cycPr C≡C—iPr 152-153 290.0950 2441 6-Cl cycPr C≡C—Ph 156-157 324.0778 2442 6-Cl cycPr C≡C—iBu 142-143 304.1102 2443 6-Cl iPr CH₂CH₂—iPr oil 296.1417 2444 6-Cl cycPr CH₂CH₂CH═CH₂ oil 278.0946 2445 6-Cl C≡C—cycPr C≡C—cycPr 129-131 312.0786 2446 6-Cl CF₃ C≡C—iBu 176-177 332.0664 2447 6-Cl C≡C—iPr C≡C—iPr 139 316.1104 2448 6-Cl iPr CH₂CH₂CH═CH₂ oil 280.1109 2449 6-Cl C≡CH C≡C—iPr 161-162 274.0638 2450 6-Cl CF₃ C(Me)₂CH═CH₂ 113-114 320.0662 2451 6-Cl CF₃ C≡C-2-Py 2452 6-Cl CF₃ C≡C—nPr 193-194 318.0500 (MH⁺) 2453 6-Cl CF₃ C≡C-1-OH—cycPr 2454 6-Cl C≡CH C≡C—Et 157-159 260.0483 2455 6-Cl CF₃ CH₂—iPr 177-178 308.0659 2456 6-Cl iPr CH₂—iPr 132-133 282.1261 2457 6-Cl cycPr CH₂—iPr 136-137 280.1104 2458 6-Cl iPr C≡C—Et amorphous 2459 6-Cl CF₃ C≡C—Et 142-146 2460 6-Cl CF₃ C≡C—Et 143-147 2461 6-Cl CF₃ CH₂CH₂—iPr amorphous 2462 6-Cl CF₃ CH₂CH₂—iPr amorphous 2463 6-Cl iPr C≡C—cycPr amorphous 2464 6-Cl iPr C≡C—cycPr amorphous 2465 6-Cl CF₃ CH₂—C≡C—Me 196-199 2466 6-Cl CF₃ CH₂—C≡C—Et 140-145 2467 6-Cl CF₃ NHCH₂CH₂CH₃ 184-185 309.0628 2468 6-Cl CF₃ C≡C-2-furanyl 170-171 2469 6-Cl CF₃ C≡C-3-thienyl 176.7-178   2470 6-Cl CF₃ C≡C-3-furanyl 155-156 2471 6-Cl CF₃ OBu 132-133 2472 6-Cl CF₃ C≡C-5-thiazolyl   196-196.5 2473 6-Cl CF₃ CH═CH-3-Py(t) 188-189 2474 6-Cl CF₃ C≡C-3-py 183.5 2475 6-Cl CF₃ C≡C-3-py 2476 6-Cl CF₃ CH═CH-iPr(t) 2477 6-Cl CF₃ CH═CH-iPr(t) 2478 6-Cl CF₃ OCH₂CH₂—iPr 338.0766 2479 6-Cl CF₃ OCH₂CH₂—OMe 127-128 326.0391 2480 6-Cl CF₃ CH═CH—cycPr(t) 136-137 2481 6-Cl CF₃ CH═CH—cycPr(t) amorphous 2482 6-Cl CF₃ CH═CH—cycPr(t) amorphous 2483 6-Cl CF₃ CH═CH—nPr(t) 127-128 2484 6-Cl CF₃ CH═CH—Et(t) 146-147 2485 6-Cl CF₃ C≡C—Me 243-244 2486 6-Cl CF₃ C≡C—iPr 116-118 2487 6-F iPr C≡C—iPr 276.1400 2488 6-F iPr C≡C—cycPr 274.1243 2489 6-F CF₃ C≡C—iPr 302.0797 2490 6-F CF₃ CH₂CH₂—iPr 306.1111 2491 6-F CF₃ C≡C—cycPr 300.0638 2492 6-F CF₃ C≡C—Ph 336.0648 2493 6-F CF₃ Pentyl 306.1106 2494 6-F CF₃ C≡C—iPr 2495 6-F CF₃ C≡C—iPr 302.0792 2496 6-F CF₃ C≡C—Et 288.0650 (MH⁺) 2497 6-F CF₃ C≡C—nPr 302.0796 2498 6-F CF₃ Butyl 292.0947 *Unless otherwise noted, stereochemistry is (+/−).

Utility

The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV inhibitory efficacy. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV infection and associated diseases. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assay described below.

The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or expected to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.

The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral clone replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.

Since the compounds of the present invention exhibit specificity for HIV reverse transcriptase, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV reverse transcriptase. Thus, inhibition of the reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of the presence of HIV reverse transcriptase and HIV virus.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram. “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nonomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar and “nm” denotes nanometer. “Sigma” stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

HIV RNA Assay

DNA Plasmids and in vitro RNA transcripts:

Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retrovirus 1989, 5, 577. The plasmid was linearized with Bam HI prior to the generation of in vitro RNA transcripts using the Riboprobe Gemini system II kit (Promega) with T7 RNA polymerase. Synthesized RNA was purified by treatment with RNase free DNAs (Promega), phenol-chloroform extraction, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at −70° C. The concentration of RNA was determined from the A₂₆₀.

Probes:

Biotinylated capture probes were purified by HPLC after synthesis on an Applied Biosystems (Foster City, Calif.) DNA synthesizer by addition of biotin to the 5′ terminal end of the oligonucleotide, using the biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287. The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCCATACTA 3′) was complementary to nucleotides 889-912 of HXB2 and the pol biotinylated capture probe (5′-biotin-CCCTATCATTTTTGGTTTCCAT 3′) was complementary to nucleotides 2374-2395 of HXB2. Alkaline phosphatase conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, Calif.). The pol reporter probe (5′ CTGTCTTACTTTGATAAAACCTC 3′) was complementary to nucleotides 2403-2425 of HXB2. The gag reporter probe (5′ CCCAGTATTTGTCTACAGCCTTCT 3′) was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Genetic Sequence Data Bank as accessed through the Genetics Computer Group Sequence Analysis Software Package (Devereau Nucleic Acid Research 1984, 12, 387). The reporter probes were prepared as 0.5 μM stocks in 2×SSC (0.3 M NaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 100 μM stocks in water.

Streptavidin coated plates:

Streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, Mass.).

Cells and virus stocks:

MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF was propagated in MT-4 cells in the same medium. Virus stocks were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at −70° C. Infectious titers of HIV-1(RF) stocks were 1-3×10⁷ PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells (see below). Each aliquot of virus stock used for infection was thawed only once.

For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells were resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2×10⁶/mL in Dulbecco's modified Eagles medium with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37° C.

HIV RNA assay:

Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5 M GED and capture probe to a final guanidinium isothiocyanate concentration of 3 M and a final biotin oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37° C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1 M and aliquots (150 μL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween 20.) A second hybridization of reporter probe to the immobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 μl of a hybridization cocktail containing 4×SSC, 0.66% Triton X 100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37° C., the plate was again washed 6 times. Immobilized alkaline phosphatase activity was detected by addition of 100 μL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer δ (2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl₂, 5 mM zinc acetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). The plates were incubated at 37° C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.

Microplate based compound evaluation in HIV-1 infected MT-2 cells:

Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum DMSO concentration of 2%. Further three-fold serial dilutions of the compound in culture medium were performed directly in U bottom microtiter plates (Nunc). After compound dilution, MT-2 cells (50 μL) were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well). Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂ incubator. For evaluation of antiviral potency, an appropriate dilution of HIV-1 (RF) virus stock (50 μL) was added to culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 μL. Eight wells per plate were left uninfected with 50 μL of medium added in place of virus, while eight wells were infected in the absence of any antiviral compound. For evaluation of compound toxicity, parallel plates were cultured without virus infection.

After 3 days of culture at 37° C. in a humidified chamber inside a CO₂ incubator, all but 25 μL of medium/well was removed from the HIV infected plates. Thirty seven μL of 5 M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M GED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37° C. incubator. Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 μL of this diluted mixture was transferred to a streptavidin coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, prepared by adding known amounts of pDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.

In order to standardize the virus inoculum used in the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC₉₀ value (concentration of compound required to reduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL. IC₉₀ values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-1 (RF) when this procedure was followed. This concentration of virus corresponded to −3×10⁵ PFU (measured by plaque assay on MT-2 cells) per assay well and typically produced approximately 75% of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, IC₉₀ values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the RNA assay relative to the net signal from infected, untreated cells on the same culture plate (average of eight wells). Valid performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. The IC₉₀ for ddC, determined in each assay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved in an uninhibited infection. A compound was considered active if its IC₉₀ was found to be less than 20 μM.

For antiviral potency tests, all manipulations in microtiter plates, following the initial addition of 2× concentrated compound solution to a single row of wells, were performed using a Perkin Elmer/Cetus ProPette.

HIV-1, RT Assay Materials and Methods

This assay measures HIV-1 RT RNA dependent DNA polymerase activity by the incorporation of 3H dTMP onto the template primer Poly (rA) oligo (dT)12-18. The template primer containing the incorporated radioactivity was separated from unincorporated label by one of two methods:

Method 1. The template primer was precipitated with TCA, collected on glass fiber filters and counted for radioactivity with a scintillation counter.

Method 2. The currently used method is more rapid and convenient. The template primer is captured on an diethyl amino ethyl (DEAE) ion exchange membrane which is then counted for radioactivity after washing off the free nucleotide.

Materials and Reagents:

The template primer Poly (rA) oligo (dT)12-18 and dTTP were purchased from Pharmacia Biotech. The template primer and nucleotide were dissolved in diethyl pyrocarbonate water to a concentration of 1 mg/ml and 5.8 mM respectively. The substrates were aliquoted (template primer at 20 μl/aliquot, dTTP at 9 μl/aliquot) and frozen at −20° C.

The 3H dTTP (2.5 mCi/ml in 10 mM Tricine at pH 7.6; specific activity of 90-120 Ci/mmol) and the recombinant HIV-1 Reverse Transcriptase (HxB2 background; 100 U/10 μl in 100 mM potassium phosphate at pH 7.1, 1 mM dithiothreitol and 50% glycerol) were purchased from DuPont NEN. 1 Unit of enzyme is defined by DuPont NEN as the amount required to incorporate 1 nmol of labelled dTTP into acid-insoluble material in 10 minutes at 37 C. The 3H dTTP was aliquoted at 23.2 μl/microfuge tube (58 μCi) and frozen at −20° C. The HIV-1 Reverse Transcriptase (RT) was diluted 10 fold with RT buffer (80 mM KCl, 50 mM Tris HCl, 12 mM MgCl2, 1 mM DTT, 50 μM EGTA, 5 mg/ml BSA, 0.01% Triton-X 100, pH 8.2) and aliquoted at 10 μl/microfuge tube (10 Units/10 μl). One aliquot (enough for 8 assays) was diluted further to 10 Units/100 μl and aliquoted into 8 tubes (1.25 Units/12.5 μl). All aliquots were frozen at −70° C.

The Millipore Multiscreen DE 96 well filter plates, multiscreen plate adaptors, and microplate press-on adhesive sealing films were purchased from Millipore. The filter plate containing 0.65 μm pore size diethyl amino ethyl cellulose (DEAE) paper disks was pretreated with 0.3 M ammonium formate and 10 mM sodium pyrophosphate (2 times 200 μl/well) at pH 8.0 prior to use. A Skatron 96 well cell harvester and glass fiber filter mats were purchased from Skatron Instruments. Microscint 20 scintillation cocktail was purchased from Packard. Beckman Ready Flow III scintillation cocktail was purchased from Beckman.

HIV-1 RT Assay:

The enzyme and substrate mixture were freshly prepared from the above stock solutions. 1.25 Units of enzyme was diluted with RT buffer (containing 5 mg/ml BSA) to a concentration of 0.05 Units/10 μl or 0.7 nM. Final enzyme and BSA concentrations in the assay were 0.01 Units or 0.14 nM and 1 mg/ml respectively. The inhibitor and substrate mixture were diluted with RT buffer containing no BSA. All inhibitors were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 3 mM and stored at −20 C after use. A Biomek robot was used to dilute the inhibitors in a 96 well plate. Inhibitors were initially diluted 96 fold from stock and then serially diluted two times (10 fold/dilution) from 31.25 μM to 3125 nM and 312.5 nM. Depending on the potency of the inhibitor, one of the three dilutions was further diluted. Typically the highest concentration (31.25 μM) was serially diluted three times at 5 fold/dilution to 6.25, 1.25, and 0.25 μM. Final inhibitor concentrations in the assay were 12.5, 2.5, 0.5, and 0.1 μM. For potent inhibitors of HIV-1 RT, the final inhibitor concentrations used were 0.1 or 0.01 that stated above. The substrate mixture contained 6.25 μg/ml of Poly (rA) oligo (dT)12-18 and 12.5 μM of dTTP (58 μCi 3H dTTP). The final substrate concentrations were 2.5 μg/ml and 5 μM respectively.

Using the Beckman Instruments Biomek robot, 10 μl of HIV-1 RT was combined with 20 μl of inhibitor in a 96 well U bottom plate. The enzyme and inhibitor were preincubated at ambient temperature for 6 minutes. 20 μl of the substrate mixture was added to each well to initiate the reaction (total volume was 50 μl). The reactions were incubated at 37 C and terminated after 45 minutes.

For method 1, 200 μl of an ice-cold solution of 13% trichloroacetic acid (TCA) and 10 mM sodium pyrophosphate was added to each of the 96 wells. The 96 well plate was then placed in an ice-water bath for 30 minutes. Using A Skatron 96 well cell harvester, the acid precipitable material was collected on a glass fiber filter mat that had been presoaked in 13% TCA and 10 mM sodium pyrophosphate. The filter disks were washed 3 times (2.0 ml/wash) with 1 N HCl and 10 mM sodium pyrophosphate. The filter disks were punched out into scintillation vials, 2.0 ml of Beckman Ready Flow III scintillant was added, and the vials were counted for radioactivity for 1 minute.

For method 2, the assay was terminated with the addition of 175 μl/well of 50 mM EDTA at pH 8.0. Then 180 μl of the mixture was transferred to a pretreated Millipore DE 96 well filter plate. Vacuum was applied to the filter plate to aspirate away the liquid and immobilize the template primer on the DEAE filter disks. Each well was washed 3 times with 200 μl of 0.3 M ammonium formate and 10 mM sodium pyrophosphate at pH 8.0. 50 μl of microscint 20 scintillation cocktail was added to each well and the plate was counted for radioactivity on a Packard Topcount at 1 minute/well.

The IC₅₀ values are calculated with the equation:

IC₅₀=[Inh]/(1/fractional activity−1)

where the fractional activity=RT activity (dpms) in the presence of inhibitor/RT activity (dpms) in the absence of inhibitor. For a given inhibitor, the IC₅₀ values were calculated for the inhibitor concentrations that range between 0.1-0.8 fractional activity. The IC₅₀ values in this range (generally 2 values) were averaged. A compound was considered active if its IC₅₀ was found to be less than 12 μM.

Protein Binding and Mutant Resistance

In order to characterize NNRTI analogs for their clinical efficacy potential the effect of plasma proteins on antiviral potency and measurements of antiviral potency against wild type and mutant variants of HIV which carry amino acid changes in the known binding site for NNRTIs were examined. The rationals for this testing strategy is two fold:

1. Many drugs are extensively bound to plasma proteins. Although the binding affinity for most drugs for the major components of human plasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein (AAG), is low, these major components are present in high concentration in the blood. Only free or unbound drug is available to cross the infected cell membrane for interaction with the target site (i.e., HIV-1 reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound in the clinical setting. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. The fold increase in apparent IC90 for test compounds in the presence or added levels of HSA and AAG that reflect in vivo concentrations (45 mg/ml HSA, 1 mg/ml AAG) was then calculated. The lower the fold increase, the more compound will be available to interact with the target site.

2. The combination of the high rate of virus replication in the infected individual and the poor fidelity of the viral RT results in the production of a quasi-species or mixtures of HIV species in the infected individual. These species will include a majority wild type species, but also mutant variants of HIV and the proportion of a given mutant will reflect its relative fitness and replication rate. Because mutant variants including mutants with changes in the amino acid sequence of the viral RT likely pre-exist in the infected individual's quasi-species, the overall potency observed in the clinical setting will reflect the ability of a drug to inhibit not only wild type HIV-1, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-1 which carry amino acid substitutions at positions thought to be involved in NNRTI binding, and measured the ability of test compounds to inhibit replication of these mutant viruses. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. It is desirable to have a compound which has high activity against a variety of mutants.

Dosage and Formulation

The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, i.e., the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions or parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 or sorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by inject can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

Combination of components (a) and (b)

Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (b) is to be understood to represent one or more agents as described previously. Thus, if components (a) and (b) are to be treated the same or independently, each agent of component (b) may also be treated the same or independently.

Components (a) and (b) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are not formulated together in a single dosage unit, the component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or they may be administered in the revserse order. If component (b) contains more that one agent, e.g., one RT inhibitor and one protease inhibitor, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart. Preferably, the route of administration of component (a) and (b) is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (a) and component (b) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.

As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

The proper dosage of components (a) and (b) of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 100 milligrams to about 1.5 grams of each component. If component (b) represents more than one compound, then typically a daily dosage may be about 100 milligrams to about 1.5 grams of each agent of component (b). By way of general guidance, when the compounds of component (a) and component (b) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of HIV infection, in view of the synergistic effect of the combination.

The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components (a) and (b) via a coating or some other material, contact may also be prevented between the individual agents of component (b).

Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.

Pharmaceutical kits useful for the treatment of HIV infection, which comprise a therapeutically effective amount of a pharmaceutical composition comprising a compound of components (a) and one or more compounds of component (b), in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as desired. Component (a) and component (b), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. 

What is claimed is:
 1. A compound of formula II:

or a salt or stereoisomer thereof, wherein: A is O or S; W is N or CR³; X is N or CR⁴; Y is N or CR⁵; Z is N or CR⁶; provided that if two of W, X, Y, and Z are N, then the remaining are other than N; R^(1a) is selected from CF₃, CF₂H, C₂F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl; R⁴ is selected from H. F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰; alternatively, R³ and R⁴ together form —OCH₂O—; R⁵ is selected from H, F, Cl, Br, and I; alternatively, R⁴ and R⁵ together form —OCH₂O—or a fused benzo ring; R⁶ is selected from H, OH, C₁₋₃ alkoxy, —CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂; R⁷ is selected from H and C₁₋₃ alkyl; R^(7a) is selected from H and C₁₋₃ alkyl; R^(7b) is C₁₋₂ alkyl; R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃; R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷R^(7a), CHO, C(O)CH₃, C(O)NH₂; p is selected from 0, 1, and
 2. 2. A compound according to claim 1, wherein: A is O; and, R^(1a) is selected from CF₃, CF₂H, C₂F₅, C₁₋₃ alkyl, C₃₋₅ cycloalkyl.
 3. A compound according to claim 2, wherein: R^(1a) is selected from CF₃, CF₂H, C₂F₅, C₂H₅, isopropyl, cyclopropyl; R³ is selected from H, F, Cl, Br, I, OCH₃, CH₃; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form —OCH₂O—; R⁵ is selected from H, F; R⁶ is selected from H, OH, OCH₃, —CN, F, CF₃, CH₃, and C(O)NH₂; R⁷ is selected from H and CH₃; R^(7a) is selected from H and CH₃; R^(7b) is CH₃; R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃; and, p is selected from 1 and
 2. 4. A compound according to claim 3, wherein: R^(1a) is selected from CF₃, CF₂H, C₂F₅; R³ is selected from H, F, Cl, Br, I; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C≡CH, OCH₃, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), C(O)OR⁷, NR⁷SO₂R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form —OCH₂O—; and, R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷R^(7a), C(O)CH₃, and C(O)NH₂.
 5. A process for making a compound of formula II:

or salt or stereoisomer thereof, comprising: (a) contacting a compound of formula III:

or a suitable salt form thereof, with a carbonyl or thiocarbonyl delivering agent in the presence of a suitable solvent, wherein: A is O or S; W is N or CR³; X is N or CR⁴; Y is N or CR⁵; Z is N or CR⁶; provided that if two of W, X, Y, and Z are N, then the remaining are other than N; R^(1a) is selected from CF₃, CF₂H, C₂F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7a), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰; alternatively, R³ and R⁴ together form —OCH₂O—; R⁵ is selected from H, F, Cl, Br, and I; alternatively, R⁴ and R⁵ together form —OCH₂O—or a fused benzo ring; R⁶ is selected from H, OH, C₁₋₃ alkoxy, —CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂; R⁷ is selected from H and C₁₋₃ alkyl; R^(7a) is selected from H and C₁₋₃ alkyl; R^(7b) is C₁₋₃ alkyl; R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃; R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷R^(7a), CHO, C(O)CH₃, C(O)NH₂; Q is selected from O, S and NH; and, p is selected from 2, 1, and
 2. 6. The process according to claim 5, wherein: A is O; R^(1a) is selected from CF₃, CH₂H, C₂F₅; R³ is selected from H, F, Cl, Br, I; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C≡CH, OCH₃, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), C(O)OR⁷, NR⁷SO₂R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form —OCH₂O—; and, R⁵ is selected from H, F; R⁶ is selected from H, OH, OCH₃, —CN, F, CF₃, CH₃, and C(O)NH₂; R⁷ is selected from H and CH₃; R^(7a) is selected from H and CH₃; R^(7b) is CH₃; R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃; R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷R^(7a), C(O)CH₃, and C(O)NH₂; and, p is selected from 1 and
 2. 7. The process according to claim 6, wherein the carbonyl delivering agent is selected from phosgene, carbonyldiimidazole, chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate.
 8. The process according to claim 7, wherein the carbonyl delivering agent is phosgene and the solvent is toluene.
 9. The process according to claim 8, wherein in step (a) a base is present and is selected from trimethylamine, triethylamine, and N,N-disopropylethylamine. 